EA027226B1 - 5-fluoro-n-(pyridin-2-yl)pyridin-2-amine derivatives containing a sulfoximine group - Google Patents

Abstract

The present invention relates to 5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a sulfoximine group of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).

Description

The invention relates to derivatives of 5-fluoro-M- (pyridin-2-yl) pyridin-2-amine containing a sulfoximine group of the general formula (I) in accordance with the description and definition herein, as well as methods for their preparation, their use for treatment and / or prevention of diseases, in particular hyperproliferative diseases, and / or viral infections, and / or diseases of the cardiovascular system. The present invention also relates to intermediates that can be used to prepare said compounds of general formula (I).

The protein family of cyclin-dependent kinases (SHOK) includes SHOK, which are key regulators of the cell division cycle (SOC of the cell cycle), SOC, which are involved in the regulation of gene transcription (transcriptional SOC), and SOC with other functions. Activation of JUICE requires association with the cyclin regulatory subunit. The cell cycle SOK, COK1 / cyclin B, COK2 / cyclin A, COK2 / cyclin E, COK4 / cyclin Ό and COK6 / cyclin Ό are activated in sequential order, as a result of which the cell division cycle is activated and carried out in the cell. The transcriptional SOK, SOK9 / cyclin T and SOK7 / cyclin N regulate the activity of RNA polymerase II by phosphorylation of the carboxy-terminal domain (STO). Positive transcription factor b (P-TEEE) is a heterodimer of COK9 and one of the four cyclin partners, cyclin T1, cyclin K, cyclin T2a or T2b.

Despite the fact that SOK9 (the number in the SeleVaik Oepe GO 1025 NСΒI database) is involved exclusively in transcriptional regulation, SOK7 is also involved in the regulation of the cell cycle as a subunit of SOK-activating kinase (SAK).

Gene transcription by RNA polymerase II is initiated by assembly of the pre-initiator complex in the promoter region and phosphorylation of § 5 and § 7 in STO using COK7 / cyclin N. For most genes, RNA polymerase II stops mRNA transcription after passing 20-40 nucleotides in the matrix DNA Such a promoter-proximal pause of RNA polymerase II occurs with the participation of negative elongation factors, and it is considered to be one of the main mechanisms for controlling the regulation of the expression of rapidly induced genes in response to many stimuli (Sko e1 a1., Ce11 Cs1e 9, 1697, 2010). P-TEEE is the most important factor involved in overcoming the promoter-proximal pause of RNA polymerase II and in the transition to productive elongation by phosphorylation of Sfet 2 in SRT, as well as by phosphorylation and inactivation of negative elongation factors.

The activity of P-TEEE itself is regulated by several mechanisms. Approximately half of the cellular P-TEEB is in an inactive complex with 7§K small nuclear RNA (7§K-snRNA), related protein 7 (ΕΑΚΡ7 / ΡΖΡ7δ) and hexamethylene-bis-acetamide-induced 1/2 proteins (HEXX1 / 2, Not e1 a1., Mo1 Ce11 29, 588, 2008). The remaining half of P-TEEE is in the active complex containing the bromodomain-containing protein Wb4 (Wapd e1 a1., Mo1 Ce11 19, 535, 2005). Wi4 mobilizes P-TEEE through interaction with acetylated histones in chromatin regions primed for gene transcription. Despite the fact that it alternately interacts with both positive and negative regulators, functional equilibrium is maintained for P-TEEB: PTEE associated with the 7K-snRNA complex is a reservoir from which active PTEE can be released if necessary for transcription in cells and cell proliferation (ΖΗοιι & У1к, МютоЬю1 Мо1 Βίο1 Кеу 70, 646, 2006). In addition, the activity of P-TEEE is regulated by post-translational modifications, including phosphorylation / dephosphorylation, ubiquitination, and acetylation (discussed in Skoe e1 a1., Ce11 Cuc1e 9, 1697, 2010).

Violation of the regulation of the activity of COX9 of the P-TEE heterodimer is associated with many pathological conditions of a person, such as, for example, hyperproliferative diseases (e.g. cancer), viral infections, or diseases of the cardiovascular system.

Cancer is a hyperproliferative disease caused by an imbalance in proliferation and cell death (apoptosis). In various tumors in humans, high levels of anti-apoptotic proteins of the Bc1-2 family are found, which are the cause of the long-term survival of tumor cells and resistance to therapy. It was proved that inhibition of the activity of P-TEE kinase reduces the transcriptional activity of RNA polymerase II, which leads to a decrease in the number of short-lived antiapoptotic proteins, in particular, Mc1-1 and XIΑΡ, which restores the ability of tumor cells to apoptosis. Some other proteins associated with the transformed tumor phenotype (such as Myc, ΝΡ-kB-dependent transcripts, mitotic kinases) are either short-lived proteins or proteins that are encoded by short-lived transcripts that are sensitive to reduced RNA polymerase II activity, which provided by inhibition of P-TEEE (reviewed in ^ APD & Iksket, Ttpeyk Rkagtaso1 δα 29, 302, 2008).

Many viruses use the transcriptional mechanism of the host cell to transcribe their own genome. In the case of SH-1, RNA polymerase II is mobilized into the promoter region in the DCT of the virus. The transcriptional activator protein (Ta!) Of the virus binds to the transcripts of the emerging virus and overcomes the promoter-proximal pause of RNA polymerase II by mobilizing P-TEE, which in turn activates transcriptional elongation. In addition, Ta! Protein increases part of the active P-TEEH by replacing the inhibiting P-TEEH HEX1 / 2 proteins in the VδK-snRNA complex. Recently obtained data show that inhibition of the kinase activity of P-TEE is sufficient

- 1 027226 to block replication of H1U-1 at kinase inhibitor concentrations that are not cytotoxic to host cells (reviewed in \ Uapd & EBsEeg Tgepbv Reattao1 8c1 29, 302, 2008). Similarly, the mobilization of P-TEE with viral proteins of other viruses, such as Epstein-Barr virus associated with B-cell cancer, is known when the nuclear antigen ΕΒΝΑ2 interacts with P-TEP (VagkPopsv e! A1., Opsodepe, 25, 1775, 2006 ), and human T-lymphotropic virus type 1 (NTLU-1), when the transcriptional activator Tax mobilizes P-TEPP (2Eoi e! a1., 1. νίτοί. 80, 4781, 2006).

Heart hypertrophy, an adaptive reaction of the heart to mechanical overload and pressure (hemodynamic stress, such as hypertension, myocardial infarction) in the long term can lead to heart failure and death. It is known that cardiac hypertrophy is associated with increased transcriptional activity and phosphorylation of STI RNA polymerase II in the cells of the heart muscle. There is evidence that P-TEPP is activated by dissociation from the inactive complex 78K-snRNA / HEX1M1 / 2. These research results suggest that pharmacological inhibition of P-TER kinase activity may be a therapeutic method for treating cardiac hypertrophy (reviewed in Yeu e! A1., Ce11 Sucl 6, 1856, 2007).

Summing up, it should be noted that there is a lot of scientific evidence that suggests that the selective inhibition of the activity of SIC9 kinase P-TEPP heterodimer (= SIC9 and one of the four cyclin partners, cyclin T1, cyclin K, cyclin T2a or T2b) is innovative an approach to the treatment of diseases such as cancer, viral diseases and / or heart disease. SIC9 belongs to the family of at least 13 related kinases, where the subgroup of the SEC of the cell cycle performs various functions in the regulation of cell proliferation. Thus, it can be assumed that the joint inhibition of the SIC of the cell cycle (for example, SIC1 / cyclin B, SIC2 / cyclin A, SIC2 / cyclin E, SIC4 / cyclin O, SIC6 / cyclin I) and SIC9 will affect proliferating normal tissues, such as, for example, the intestinal mucosa, organs of the lymphatic system, and blood-forming organs and genitals. To maximize the breadth of the therapeutic effect of SIC9 kinase inhibitors, molecules with high selectivity for SIC9 are needed.

In general, SIC inhibitors as well as SIC9 inhibitors are described in many different publications.

The documents νθ 2008129070 and νθ 2008129071 describe 2,4-disubstituted aminopyridines as inhibitors of SIR in general. It is also argued that some of these compounds may act as selective inhibitors of CIC9 (νθ 2008129070) and CIC5 inhibitors (νθ 2008129071), respectively, however, specific data on 1C ₅₀ CIC9 (νθ 2008129070) or 1C ₅₀ CIC5 (νθ 2008129071) are not presented . These compounds do not contain a fluorine atom at the 5-position of the pyrimidine nucleus.

Document νθ 2008129080 describes 4,6-disubstituted aminopyridines and shows that these compounds exhibit an inhibitory effect on the activity of various protein kinases, such as CIC1, CIC2, CIC4, CIC5, CIC6 and CIC9, preferably exhibit inhibition of CIC9 (Example 80).

Document νθ 2005026129 describes 4,6-disubstituted aminopyridines and shows that these compounds exert an inhibitory effect on the activity of various protein kinases, in particular CIC2, CIC4 and CIC9.

The νθ 2011116951 document describes substituted triazine derivatives as selective inhibitors of SIC9.

Document νθ 2012117048 describes disubstituted triazine derivatives as selective inhibitors of SIC9.

Document νθ 2012117059 describes disubstituted pyridine derivatives as selective inhibitors of SIC9.

Νθ 2012143399 describes substituted 4-aryl ^ phenyl-1,3,5-triazin-2-amines as selective inhibitors of SIC9.

EP 1218360 B1, which corresponds to I8 2004116388 Α1, I8 7074789 Β2 and νθ 2001025220 Α1, describes triazine derivatives as kinase inhibitors, however, highly active or selective CIC9 inhibitors are not described.

Derivatives of aminopyridine and aminopyrimidine and their use as inhibitors of CIC1, CIC2, CIC3, CIC4, CIC5, CIC6, CIC7, CIC8 or CIC9 are described in νθ 2008079933.

The νθ 2011012661 document describes aminopyridine derivatives which are used as SIC inhibitors.

Νθ 2011026917 describes carboxamides derived from substituted 4-phenylpyridin-2-amines as inhibitors of SIC9.

Document νθ 2012066065 describes phenylheteroarylamines as inhibitors of SIC9. Selectivity to SIC9 in relation to other SIC isoforms is preferred, however, the SIC inhibition data provided in the description of the invention are limited exclusively to SIC

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9. Bicyclic ring systems attached in the C4 position to the pyrimidine nucleus are not described. It can be assumed that alkoxyphenyls in the group attached to the C4 pyrimidine nucleus are included in the scope of the invention, however, there is no indication of a specific substitution pattern, which is characterized by the fact that the fluorine atom is attached to the C5 of the pyrimidine nucleus and the aniline to C2 of the pyrimidine, where the substituted group sulfonyl methylene is in the meta position. In the compounds shown in the Examples section, a substituted cycloalkyl group is represented as K ¹ , and phenyl is absent.

Document UO 2012066070 describes 3- (aminoaryl) pyridine compounds as ECC9 inhibitors. The biaryl core necessarily consists of two heteroaromatic rings.

Document UO 2012101062 describes compounds of substituted bigheteroaryl in which there is a 2-aminopyridine nucleus as inhibitors of ECC9. The biaryl core necessarily consists of two heteroaromatic rings.

UO 2012101063 describes carboxamides derived from substituted 4- (heteroaryl) pyridin-2-amines as inhibitors of ECC9.

UO 2012101064 describes Ν-acylpyrimidine biaryl compounds as inhibitors of ECC9.

Document UO 2012101065 describes pyrimidine biaryl compounds as inhibitors of SEC9. The biaryl core necessarily consists of two heteroaromatic rings.

The document \ UO 2012101066 describes pyrimidine biaryl compounds as inhibitors ί'.ΌΙ <9. Substitution of the K ¹ amino group attached to the heteroaromatic nucleus is limited to non-aromatic groups, but does not cover substituted phenyls. In addition, the biaryl core necessarily consists of two heteroaromatic rings.

In the document \ UO 2013037896, disubstituted 5-fluoropyrimidines are described as selective inhibitors ί'.ΌΙ <9.

Document UO 2013037894 describes derivatives of disubstituted 5-fluoropyrimidine containing a sulfoximine group as selective inhibitors ί'.ί <9.

WAPD c (a1. (SNSTMGU & Vyuodu 17, 1111-1121, 2010) describes transcriptional COX inhibitors based on 2-anilino-4- (thiazol-5-yl) pyrimidine, which exhibit anti-cancer activity in animal models.

Document UO 2004009562 describes kinase inhibitors based on substituted triazines. For the selected compounds, research data on SEC1 and SEC4 are given. however, no data are provided for SEC9.

Document UO 2004072063 describes pyrroles heteroaryl (pyrimidine, triazine) substituted as protein kinase inhibitors, such as EKK2, O8K3, PKA or SEC2.

In the document \ UO 2010009155 derivatives of triazine and pyrimidine are described as inhibitors of histone deacetylase and / or cyclin-dependent kinases (RNCs). For the selected compounds, research data on ί'.ΌΙ <2 are presented.

Document UO 2003037346 (which corresponds to I87618968B2, I87291616B2, I82008064700A1, I8 2003153570 A1) relates to aryl triazines and methods for their use, including inhibition of the activity of acyltransferase-beta lysophosphatidic acid (bRAAT-beta cells) and / or.

UO 2005037800 describes sulfoximine substituted anilino-pyrimidines as inhibitors of UEORK and SOK kinases, in particular UEORK2, SEC1 and SEC2, which do not have an aromatic ring directly bonded to the pyrimidine ring and which have a sulfoximine group directly bonded to anilines group. Data on ί'.ΌΙ <9 are not given.

The document \ UO 2008025556 describes carbamoyl sulfoximides with a pyrimidine core, which can be used as kinase inhibitors. Data on ί'.ΌΙ <9 are not given. Examples of molecules with a fluoropyrimidine nucleus are not given.

In the document \ UO 2002066481 pyrimidine derivatives are described which are used as inhibitors of cyclin-dependent kinases. ί'.ΌΙ <9 is not mentioned, and data on SEC9 are not provided.

Document \ UO 2008109943 relates to phenylaminopyridine compounds and to their use as kinase inhibitors, in particular, as 1AK2 kinase inhibitors. In specific examples, attention is focused mainly on compounds with the pyrimidine nucleus.

The document \ UO 2009032861 describes substituted pyrimidinylamines which are used as inhibitors of 1ΝΙ <kinase. In specific examples, attention is focused mainly on compounds with the pyrimidine nucleus.

Document \ UO 2011046970 relates to aminopyrimidine compounds which are used as TBKb and / or 1KK epsilon inhibitors. In specific examples, attention is focused mainly on compounds with the pyrimidine nucleus.

Document \ UO 2012142329 relates to aminopyrimidine compounds which are used

- 3,027,226 as inhibitors of TBTV and / or ΙΚΚ epsilon.

U.S. Patent No. 2012139499 describes urea-substituted anilinopyrimidines as inhibitors of various protein kinases.

Although many SEC inhibitors are known, there remains a need for selective SEC 9 inhibitors that could be used to treat diseases, such as hyperproliferative diseases, viral diseases and / or heart diseases, which, compared to prior art compounds, provide would have one or more advantageous characteristics:

improved activity and / or effectiveness;

more effective kinase selectivity profile according to therapeutic needs;

an improved side effect profile, for example fewer undesirable side effects, reduced side effects or reduced (cyto) toxicity, for example, by reducing inhibition of carbonic anhydrase;

improved physico-chemical characteristics, such as solubility in body fluids and in water-based formulations, for example, for intravenous administration;

improved pharmacokinetic characteristics, which would provide, for example, the possibility of reducing the dose or less complicated dosage regimen;

the possibility of a simpler manufacture of the drug, for example, as a result of using less complex synthesis methods or simpler purification methods.

A specific object of the invention is the provision of SG) K9 kinase inhibitors which, compared to compounds in accordance with the prior art, would demonstrate increased selectivity for SEC9 / cyclin T1 compared to SEC2 / cyclin E.

Another object of the invention is the provision of AG) K9 kinase inhibitors that would exhibit increased activity on the inhibition of SG) K9 (as shown by a lower value of 1C ₅₀ for SEC9 / cyclin T1) compared with the compounds of the prior art.

Another objective of the invention is the provision of inhibitors of SG) K9 kinase, which would demonstrate increased activity inhibition of SEC9 at high concentrations of ATP compared with compounds in accordance with the prior art.

Another object of the invention is the provision of SG) K9 kinase inhibitors that would exhibit improved antiproliferative activity in tumor cell lines, such as HeLa, as compared with compounds of the prior art.

The objective of the invention is the provision of inhibitors of SG) K9 kinase, which, compared with compounds in accordance with the prior art, would show increased selectivity for SEC9 / cyclin T1 compared to SEC2 / cyclin E, and / or which would show increased activity for inhibition of SEC9 , and / or that would exhibit increased antiproliferative activity in tumor cell lines, such as HeLa, and / or that would exhibit increased activity for inhibition of SG) K9 at high concentrations tions ATP as compared with the compounds in accordance with the prior art.

The present invention relates to compounds of the general formula (I)

where K ¹ represents a group selected from C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, heterocyclyl, phenyl, heteroaryl, phenyl-C ₁ -C ₃ -alkyl or heteroaryl-C ₁ -C ₃ -alkyl wherein said group is optionally substituted, equally or differently, with one, two, or three substituents selected from the group of hydroxy, cyano, halogen, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₆ alkoxy, C ₁ -C _3- fluoroalkoxy, -YN ₂ , alkylamino, dialkylamino, acetylamino, Y-methyl-Y-acetylamino, cyclic amines, -OR (O) (OH) ₂ , -C (O) OH, -C (O) Eun ₂ ;

K ² represents a group selected from

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K ^3, K ⁴ represent, independently of each other, a group selected from a hydrogen atom, a fluorine atom, chlorine atom, bromine atom, cyano, _C1-C3 alkyl, _C1-C3 alkoxy, halo-C1-C ₃ -alkyl, C _G C ₃ fluoroalkoxy;

K ⁵ represents a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —5 (O) 2K ⁹ , —C (O) LK ¹⁰ K ¹¹ , —P ( O) (OK ¹² ) 2, -CH ₂ Op (OK ¹² ) ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, heteroaryl, where the specified C ₁ -C _{6 is} alkyl, The C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl or heteroaryl group, if necessary, is substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, cyano, C ₁ -C ₃ alkyl, C ₁ - C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl-I-acetylamino, cyclic their amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ fluoroalkoxy;

K ⁶ , K ⁷ represent, independently of each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halo-C ₁ -C ₃ - alkyl, C ₁ -C ₃ fluoroalkoxy;

K ⁸ represents a group selected from:

a) C ₁ -C ₆ -alkyl group, which, if necessary, is substituted equally or differently by one, two, or three substituents selected from halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl I-acetylamino, cyclic amines, cyano, C ₁ -C ₃ alkyl, halo C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy, C ₂ -C ₃ alkenyl, C ₂ -C ₃ -alkynyl, C ₃ -C ₇ -cycloalkyl, heterocyclyl, phenyl, heteroaryl, wherein said C3-C7 cycloalkyl, heterocyclyl, phenyl or heteroaryl group, optionally substituted, identically yl differently one, two or three substituents selected from halo, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ _2, alkylamino, dialkylamino, acetylamino, №metil-№atsetilamino, cyclic amines, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy;

b) a C ₃ -C ₇ cycloalkyl group which, if necessary, is substituted equally or differently with one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ2, alkylamino, dialkylamino, acetylamino, methyl I-acetylamino, cyclic amines, cyano, C ₁ -C ₃ alkyl, halo C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy, C ₂ -C ₃ alkenyl C ₂ -C ₃ alkynyl;

c) a heterocyclyl group, which, if necessary, is substituted equally or differently by one, two, or three substituents selected from the group of halogen, hydroxy,-,2, alkylamino, dialkylamino, acetylamino, methyl-I-acetylamino, cyclic amines , cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy, C ₂ -C ₃ -alkenyl, C ₂ -C ₃ alkynyl;

ά) a phenyl group, which, if necessary, is substituted equally or differently by one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ2, alkylamino, dialkylamino, acetylamino, methyl-I-acetylamino, cyclic amines , cyano, C ₁ -C ₃ alkyl, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy;

f) a heteroaryl group, which, if necessary, is substituted equally or differently by one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl-N-acetylamino, cyclic amines , cyano, C ₁ -C ₃ alkyl, halo-C ₁ C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy;

ί) a phenyl-C ₁ -C ₃ -alkyl group, the phenyl group of which, if necessary, is substituted equally or differently with one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino , acetylamino, N-methyl-N-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy;

e) a heteroaryl-C ₁ -C ₃ -alkyl group, in which, if necessary, the heteroaryl group is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino , acetylamino, N-methyl-N-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy;

j) a C ₃ -C ₆ cycloalkyl-C ₁ -C ₃ alkyl group, a C ₃ -C ₆ cycloalkyl group in which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from halogen, C ^ C ^ alkyl, C _g C ₃ alkoxy, halo C _g C ₃ alkyl, C _g C ₃ fluoroalkoxy;

ΐ) a heterocyclyl-C1-C ₃ -alkyl group, the heterocyclyl group of which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ - C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy;

K ⁹ represents a group selected from C ₁ -C ₆ alkyl, halo-C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted , the same or different, with one, two or three substituents selected from halogen, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, ^ methyl- ^ acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ C3-fluoroalkoxy;

K ¹⁰ , K ¹¹ represent, independently from each other, a group selected from hydrogen, C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, where the specified C ₁ -C _{6 is} alkyl, A C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C ₁ -C ₃ alkyl, C ₁ - C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, ^ methyl- ^ acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ C3 fluoroalkoxy, or

K ¹⁰ and K ¹¹ together with the nitrogen atom to which they are attached form a cyclic amine;

To ¹² represents a group selected from hydrogen, C ₁ -C ₄ -alkyl or benzyl, as well as to enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

The present invention relates to compounds of the general formula (I)

where K ¹ represents a group selected from C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, heterocyclyl, phenyl, heteroaryl, phenyl-C ₁ -C ₃ -alkyl or heteroaryl-C ₁ -C ₃ -alkyl wherein said group is optionally substituted equally or differently with one, two, or three substituents selected from the group of hydroxy, cyano, halogen, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₃ fluoroalkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl-I-acetylamino, cyclic amines, -OR (O) (OH) ₂ , -C (O) OH, -C (O) HH2;

K ² represents a group selected from

K ³ , K ⁴ represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ fluoroalkoxy;

K ⁵ represents a group selected from a hydrogen atom, cyano, -C (O) K ⁹ , -C (O) OK ⁹ , -5 (O) 2K ⁹ , -C (O ^ K ¹⁰ K ^p , -P ( O) (OK) 2, -CH ₂ OR (OK) ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, heteroaryl, where the specified C ₁ -C _{6 is} alkyl, C ₃ -C ₇ -cycloalkyl, heterocyclyl, phenyl or heteroaryl group, if necessary, substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ alkoxy, -ΝΗ _2, alkylamino, dialkylamino, acetylamino, №metil-N-acetylamino, cyclic am new, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ fluoroalkoxy;

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K ⁶ , K ⁷ represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C-Cz-alkyl, C-Cz-alkoxy, halo-C-Cz-alkyl, C-Cz- fluoroalkoxy;

K ⁸ represents a group selected from:

a) _C1-C6 alkyl group, which optionally substituted identically or differently, one or two, or three substituents selected from halo, hydroxy, -ΝΗ _two, alkylamino, dialkylamino, acetylamino, ^ methyl ^ - acetylamino, cyclic amines, cyano, C ₁ -C ₃ alkyl, halo C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy, C ₂ -C ₃ alkenyl, C ₂ -C ₃ -alkynyl, C ₃ -C ₇ -cycloalkyl, heterocyclyl, phenyl, heteroaryl, wherein said Cs-C7 cycloalkyl, heterocyclyl, phenyl or heteroaryl group, optionally substituted, identically or azlichno, one, two or three substituents selected from halo, hydroxy, C1 -C3 alkyl, C1 -C3 alkoxy, -ΝΗ2, alkylamino, dialkylamino, acetylamino, ^ methyl ^ acetylamino, cyclic amines, halo-C ₁ - C ₃ -alkyl; C ₁ -C ₃ fluoroalkoxy;

b) a C ₃ -C ₇ cycloalkyl group which, if necessary, is substituted equally or differently with one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ2, alkylamino, dialkylamino, acetylamino, methyl ^ acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy, C ₂ -C ₃ -alkenyl, C ₂ -C ₃ alkynyl;

c) a heterocyclyl group, which, if necessary, is substituted equally or differently by one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, ^ methyl- ^ acetylamino, cyclic amines , cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy, C ₂ -C ₃ -alkenyl, C ₂ -C ₃ alkynyl;

b) a phenyl group, which, if necessary, is substituted equally or differently by one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ2, alkylamino, dialkylamino, acetylamino, ^ methyl- ^ acetylamino, cyclic amines, cyano, C ₁ -C ₃ alkyl, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy;

f) a heteroaryl group, which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl- ^ acetylamino, cyclic amines , cyano, C ₁ -C ₃ alkyl, halo-C ₁ C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy;

ί) a phenyl-C ₁ -C ₃ -alkyl group, the phenyl group of which, if necessary, is substituted equally or differently with one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino , acetylamino, ^ methyl- ^ acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy;

e) a heteroaryl-C ₁ -C ₃ -alkyl group, in which, if necessary, the heteroaryl group is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino , acetylamino, ^ methyl- ^ acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy;

1ι) a C ₃ -C ₆ cycloalkyl-C ₁ -C ₃ -alkyl group, a C ₃ -C ₆ -cycloalkyl group in which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy;

ί) a heterocyclyl-C ₁ -C ₃ -alkyl group, in which, if necessary, the heterocyclyl group is substituted, equally or differently, with one, two, or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy;

K ⁹ represents a group selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted, the same or different, with one, two or three substituents selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, -ΝΗ2, alkylamino, dialkylamino, acetylamino, ^ methyl ^ -acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ C3 fluoroalkoxy;

K ¹⁰ , K ¹¹ represent, independently from each other, a group selected from hydrogen, C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, where the specified C ₁ -C _{6 is} alkyl, A C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C ₁ -C ₃ alkyl, C ₁ - C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl ^ -acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ C3 fluoroalkoxy, or

K ¹⁰ and K ¹¹ together with the nitrogen atom to which they are attached form a cyclic amine; as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

The compounds of the present invention are compounds of formula (I), as well as their salts, solvates and solvates of salts, compounds according to the formulas below in this document, covered by formula (I), as well as their salts, solvates and solvates of salts, and compounds covered by formula (I), which are listed below as examples of embodiments of the invention, as well as their salts, solvates and solvates of salts, where the compounds covered by formula (I) and indicated below in the text of this document are not already salts, solvates and solvates of salts.

Depending on their structure, the compounds of the present invention may exist in stereoisomeric forms (enantiomers, diastereoisomers). Thus, the invention relates to enantiomers or diastereoisomers, as well as their respective mixtures. From such mixtures of enantiomers and / or diastereoisomers, stereoisomerically pure components can be isolated in a known manner.

If the compounds of the present invention may be present in the form of tautomers, the present invention includes all tautomeric forms.

Also, the compounds of the present invention may be present in free form, for example, in the form of a free base or free acid, or in the form of a zwitterion or in the form of salts. Said salt may be any salt, for example, an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmaceuticals.

For the purposes of the present invention, physiologically acceptable salts of the compounds of the present invention are preferred salts. However, this also includes salts that are themselves not suitable for pharmaceutical use, but which can be used, for example, to isolate or purify the compounds of the present invention.

The term pharmaceutically acceptable salt means relatively non-toxic inorganic or organic acid addition salts of the compounds of the present invention, for example, see 8. M. Vegde, e1 a1. Ryattaseijs1 8a115, 1. Ryatt. 8st 1977, 66, 1-19.

Physiologically acceptable salts of the compounds of the present invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, hydrogen iodide, sulfuric, sulfurous, orthophosphoric, nitric acid, or organic acids, such as as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, oily, nylon, heptane, undecane, lauric, benzoic, salicylic, 2- (4-hydroxybenzoyl) benzoic, camphor phenylacrylic, cyclopentane propionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoyic, pectin, supra-sulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonic sulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonesulfonate methanesulfonic, 2-naphthalenesulfonic, naphthalene disulfonic acid, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric I, Ό-gluconic, almond, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemiseric or thiocyanic acid.

Physiologically acceptable salts of the compounds of the present invention also include salts of conventional bases, preferably such as, for example, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), as well as ammonium salts, obtained from ammonia or organic amines with 1-16 carbon atoms, for example, preferably from ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, proc ina, dibenzylamine, Ν-methylmorpholine, arginine, lysine, ethylenediamine, Ν-methylpiperidine, Ν-methylglucamine, dimethylglucamine, ethylglucamine, 1,6-hexadiamine, glucosamine, sarcosine, serinol, tris (hydroxymethanamine aminophenolamine) amino 2,3,4-butanetriol. In addition, the compounds of the present invention can form salts with a quaternary ammonium ion, which can be obtained, for example, by quaternizing a basic group containing nitrogen, using substances such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides. Examples of suitable quaternary ammonium ions are tetramethylammonium, tetraethylammonium, tetra (n-propyl) ammonium, tetra (n-butyl) ammonium or ^ benzyl-HH ^ trimethylammonium.

The present invention includes all possible salts of the compounds of the present invention, such as single salts or mixtures of these salts, in any ratio.

In the context of the present invention, the term solvates is applied to those forms of the compounds of the present invention which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, hydrates are preferred solvates.

The invention also includes all relevant isotopic variations of the compound of the invention. The isotopic variation of a compound of the present invention is defined as a compound where at least one atom is replaced by an atom with the same atomic number, but its atomic mass is different from the atomic mass of this element, which is usually or mainly found in

- 8 027226 nature. Examples of isotopes that may be contained in a compound of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² N (deuterium), ³ N (tritium), ¹³ C , ¹⁴ C, ¹⁵ Ν, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ 8, ³⁴ 8, ³⁵ 8, ³⁶ 8, ¹⁸ P, ³⁶ C1, ⁸² Vg, ¹²³ 1, ¹²⁴ 1, ¹²⁹ 1 and ¹³¹ 1 respectively. Certain isotopic variations of the compounds of the present invention, for example, compounds that contain one or more radioactive isotopes, such as H or C, can be used in tissue distribution studies of drugs and substrates. Particularly preferred are tritium labeled isotopes and carbon-14, i.e. ¹⁴ C, due to the ease of preparation and high ability to detect. Also, substitution with isotopes such as deuterium can provide certain therapeutic advantages due to the increased resistance of the compounds to inactivation during the metabolism, for example, due to the increased half-life of ίη νίνο or due to reduced dosage requirements; therefore, under certain conditions, isotope substitution may be preferred. Isotopic variations of the compounds of the present invention can generally be obtained using standard procedures known to those skilled in the art, for example, the illustrative methods or preparation methods described in the Examples section below, using appropriate isotopic variations of the applicable reagents.

In addition, the present invention also includes prodrugs of the compounds of the present invention. The term prodrugs includes compounds that, on their own, may or may not have biological activity, but, once ingested, are converted to the compounds of the invention (e.g., by metabolism or hydrolysis).

In addition, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, both individual polymorphs and mixtures containing several polymorphs, in any ratio.

Accordingly, the present invention includes all possible salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g. esters) of the compounds of the present invention, and diastereoisomeric forms of the compounds of the present invention in the form of separate salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g., esters) of the compounds of the present invention, or a diastereoisomeric form in the form of a mixture of several salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g., complex esters) of the compounds of the present invention, or the diastereoisomeric form in any ratio.

For the purposes of the present invention, substituents, unless otherwise indicated, have the following meanings:

The terms halogen, halogen atom or halo mean fluoro, chloro, bromo and iodo, in particular chloro or fluoro, preferably fluoro.

The term alkyl refers to a linear or branched alkyl radical with several carbon atoms, the number of which is specifically indicated, for example, C ₁ -C ₁₀ : one, two, three, four, five, six, seven, eight, nine or ten carbon atoms, for example , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl-, decyl-, 2-methylbutyl, 1-methylbutyl, 1 ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylb Utyl, 3,3dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl and 1,2dimethylbutyl. If the number of carbon atoms is not specifically specified, the term alkyl refers to a linear or branched alkyl radical, typically with 1 to 9, in particular 1-6, preferably 1-4 carbon atoms. In particular, the alkyl group has 1, 2, 3, 4, 5, or 6 carbon atoms (C ₁ -C ₆ alkyl), for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl , isopentyl, hexyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl , 1-ethylbutyl, 3,3dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2dimethylbutyl. Preferably, the alkyl group has 1, 2 or 3 carbon atoms (C ₁ -C ₃ -alkyl), methyl, ethyl, n-propyl or isopropyl.

The term C ₂ -C ₆ alkenyl should preferably be understood to mean a linear or branched, monovalent hydrocarbon group which contains one double bond and which contains 2 or 3 carbon atoms (C ₂ -C ₃ alkenyl). Said alkenyl group is, for example, a vinyl, allyl, (E) -2-methylvinyl, (2) -2-methylvinyl or isopropenyl group.

The term C ₂ -C ₆ alkynyl should preferably be understood to mean a linear monovalent hydrocarbon group that contains one triple bond and which contains 2 or 3 carbon atoms. Said C2-C3 alkynyl group is, for example, an ethynyl, prop-1-ynyl or prop-2-ynyl group.

The term C ₃ -C ₇ cycloalkyl should preferably be understood as a ring of a saturated, monovalent, monocyclic hydrocarbon that contains 3, 4, 5, 6 or 7 carbon atoms. Said C ₃ -C ₇ cycloalkyl group is, for example, a monocyclic hydrocarbon ring, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl

- 9 027226 group. The specified cycloalkyl ring is non-aromatic, but may, if necessary, contain one or more double bonds, for example, represent cycloalkenyl, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl group, where the bond between the specified ring and the rest of the molecule can be via any carbon atom of said ring, whether it is saturated or unsaturated. In particular, said cycloalkyl group is a C ₄ -C ₆ cycloalkyl, C ₅ -C ₆ cycloalkyl or cyclohexyl group.

By the term “C ₃ -C ₅ cycloalkyl” is meant a ring of a saturated, monovalent, monocyclic hydrocarbon that contains 3, 4 or 5 carbon atoms. In particular, said C ₃ -C ₅ cycloalkyl group is a monocyclic hydrocarbon ring, for example a cyclopropyl, cyclobutyl or cyclopentyl group. Preferably, said C ₃ -C ₅ cycloalkyl group is a cyclopropyl group.

By the term C ₃ -Cb cycloalkyl is meant a ring of a saturated, monovalent, monocyclic hydrocarbon that contains 3, 4, 5 or 6 carbon atoms. In particular, said C ₃ C ₆ cycloalkyl group is a monocyclic hydrocarbon ring, for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The term C ₃ -C ₆ cycloalkyl-C ₁ -C ₃ -alkyl is preferably understood to mean a C ₃ -C ₆ cycloalkyl group as defined above, where one of the hydrogen atoms is substituted with a C ₁ -C ₃ -alkyl group as defined above, which combines a C ₃ -C ₆ cycloalkyl-C ₁ -C ₃ alkyl group with a molecule. In particular, the C ₃ -C ₆ cycloalkyl-C ₁ -C ₃ -alkyl represents a C ₃ -C ₆ -cycloalkyl-C ₁ -C ₂ -alkyl, preferably represents a C3-C6-cycloalkyl-methyl group.

The term heterocyclyl should be understood as a ring of a saturated or partially unsaturated, monovalent, mono- or bicyclic hydrocarbon that contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and also one, two or three groups with a heteroatom selected from oxygen sulfur, nitrogen. In particular, the term heterocyclyl should be understood to mean a 4-10 membered heterocyclic ring.

The term 4-10 membered heterocyclic ring should be understood as a ring of a saturated or partially unsaturated, monovalent, mono- or bicyclic hydrocarbon which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and also one, two or three groups with a heteroatom selected from oxygen, sulfur, nitrogen. By the term C ₃ -C ₉ heterocyclyl is meant heterocyclyl which contains at least 3, 4, 5, 6, 7, 8 or 9 carbon atoms and, in addition, at least 1 heteroatom as ring atoms. Accordingly, in the case of one heteroatom, the ring is 410-membered, in the case of two heteroatoms, the ring is 5-11-membered, and in the case of three heteroatoms, the ring is 6-12-membered.

Said heterocyclic ring is, for example, a monocyclic heterocyclic ring such as oxetanyl, azetinidyl, tetrahydrofuranyl, pyrrolidinyl, 1,3-dioxolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, 1,4-dioxanyl, pyrrolidinyl pyrrolinyl , 3-dithianil, thiomorpholinyl, piperazinyl or quinuclidinyl group. If necessary, the specified heterocyclic ring may contain one or more double bonds, for example, 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, 1,3-dioxolyl, 4H-1,3,4thiadisinyl, 2, 5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothienyl, 2,3-dihydrothienyl, 4,5-dihydroxazolyl, 4,5-dihydroisoxazolyl or a 4H-1,4-thiazinyl group, or it may be a benzo compound.

In particular, the term “C ₃ -C ₇ heterocyclyl” means heterocyclyl which contains at least 3, 4, 5, 6 or 7 carbon atoms and, in addition, at least 1 heteroatom as ring atoms. Accordingly, in the case of one heteroatom, the ring is 4-8 membered, in the case of two heteroatoms the ring is 5-9-membered, and in the case of three heteroatoms the ring is 610-membered.

In particular, the term “C3-C6 heterocyclyl” means heterocyclyl which contains at least 3, 4, 5 or 6 carbon atoms and, in addition, at least 1 heteroatom as ring atoms. Accordingly, in the case of one heteroatom, the ring is 4-7-membered, in the case of two heteroatoms, the ring is 5-8-membered, and in the case of three heteroatoms, the ring is 69-membered.

In particular, the term heterocyclyl should be understood as a heterocyclic ring that contains 3, 4 or 5 carbon atoms and 1, 2 or 3 of the aforementioned groups with a heteroatom (4-8 membered heterocyclic ring), more specifically, said ring may contain 4 or 5 carbon atoms and 1, 2 or 3 aforementioned groups with a heteroatom (5-8 membered heterocyclic ring), more specifically, said heterocyclic ring is a 6 membered heterocyclic ring, which should be understood as a ring that contains 4 carbon atoms 2 above groups with heteroatom or 5 carbon atoms and one heteroatom from the above group, preferably 4 carbon atoms and 2 above groups with heteroatom.

The term _{heterocyclyl-C1-C3} alkyl group should preferably be understood heterocyclyl, preferably 4-7 membered heterocyclic ring, more preferably 5-7 membered

- 10 027226 heterocyclic ring as defined above, wherein one of the hydrogen atoms substituted with C1-Cs alkyl group, as defined above, which connects heterocyclyl-C ₁ -C ₃ -alkyl group with a molecule. In particular, heterocyclyl-C ₁ -C ₃ -alkyl is a heterocyclyl-C ₁ -C ₂ -alkyl, preferably a heterocyclyl-methyl group.

The term “C ₁ -C ₆ alkoxy” should preferably mean a linear or branched, saturated, monovalent hydrocarbon group of the formula —O-alkyl, where the term alkyl is to be understood as defined above, for example, methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, nbutoxy, isobutoxy, tert-butoxy, sec-butoxy, pertyloxy, isopertyloxy, n-hexyloxy group or isomer of these compounds. In particular, the C ₁ -C ₆ alkoxy group is a C ₁ -C ₄ alkoxy, C ₁ -C ₃ alkoxy, methoxy, ethoxy, propoxy group, preferably a methoxy, ethoxy or propoxy group. More preferably, a C ₁ -C ₂ alkoxy group, in particular a methoxy or ethoxy group.

The term C ₁ -C ₃ fluoroalkoxy should preferably be understood as a linear or branched, saturated, monovalent C1-C3 alkoxy group as defined above, and wherein one or more hydrogen atoms are identical or differently substituted with one or more fluorine atoms. Said C ₁ -C ₃ fluoroalkoxy group is, for example, 1,1-difluoromethoxy, 1,1,1 trifluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, in in particular a C ₁ -C ₂ fluoroalkoxy group.

The term alkylamino is preferably understood to mean an alkylamino group with one linear or branched alkyl group, as defined above. (C ₁ -C ₃ ) -alkylamino means, for example, a monoalkylamino group with 1, 2 or 3 carbon atoms, (C ₁ -C ₆ ) -alkylamino with 1, 2, 3, 4, 5, or 6 carbon atoms. The term alkylamino includes, for example, methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino or n-hexylamino.

The term dialkylamino is preferably understood to mean an alkylamino group with two linear or branched alkyl groups, as defined above, which are independent of each other. A (C ₁ -C ₃ ) dialkylamino is, for example, a dialkylamino group with two alkyl groups, each of which has 1-3 carbon atoms per alkyl group. The term dialkylamino includes, for example: Ν, Ν-dimethylamino, Ν, Ν-diethylamino, Y-ethyl-Y-methylamino, Ν methyl-Y-n-propylamino, H-isopropyl-N-n-propylamino. Ν-tert-butyl-N-methylamino, ethyl-L-npentylamino and N-n-hexyl-N-methylamino.

By the term cyclic amine is meant a cyclic amine group. Preferably, the cyclic amine means a saturated monocyclic group with 4-10, preferably 4-7 ring atoms, of which at least 1 ring atom is a nitrogen atom. Suitable cyclic amines are, in particular, azetidine, pyrrolidine, piperidine, piperazine, 1methylpiperazine, morpholine, thiomorpholine, which, if necessary, may be substituted with one or two methyl groups.

The term halo-C ₁ -C ₃ -alkyl or C ₁ -C ₃ -haloalkyl (used interchangeably) is preferably understood to mean a linear or branched, saturated, monovalent hydrocarbon group, where the term C ₁ -C ₃ -alkyl is to be understood as defined above, and where one or more hydrogen atoms are identical or differently substituted by a halogen atom, i.e. one halogen atom is independent of the other. In particular, said halogen atom is fluorine. A preferred halo-C ₁ -C ₃ alkyl group is a fluoro-C ₁ -C ₃ -alkyl group, such as, for example, —CH ₃ , —CHP ₂ , —CH ₂ P, —CH ₂ CP _3, or —CH ₂ CP ₃ , preferably CP ₃ .

The term phenyl-C ₁ -C ₃ -alkyl should preferably be understood as a phenyl group, where one of the hydrogen atoms is substituted by a C ₁ -C ₃ -alkyl group, as defined above, which connects the phenyl-C ₁ -C ₃ -alkyl group with a molecule. In particular, phenyl-C ₁ -C ₃ -alkyl represents a phenyl-C ₁ -C ₂ -alkyl, preferably benzyl-methyl group.

The term heteroaryl is preferably understood to mean a monovalent aromatic ring system with 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (5-14 membered heteroaryl group), in particular with 5 (5 membered heteroaryl) or 6 (6-membered heteroaryl) or 9 (9-membered heteroaryl) or 10 ring atoms (10-membered heteroaryl), and which contains at least 1 heteroatom, which may be identical or different, and such a heteroatom may be for example, an oxygen, nitrogen or sulfur atom, and, in addition, in each case, can be benzocondensed. In particular, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, etc. and benzene derivatives of these compounds, such as, for example, benzofuranyl, benzothienyl, benzooxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridylyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzene derivatives of these compounds, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc .; or azocinyl, indolisinyl, purinyl, etc. and gas derivatives of these compounds; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl, etc. Preferably, heteroaryl is selected from monocyclic heteroaryl, 5-membered heteroaryl or 6-membered heteroaryl.

- 11 027226

The term 5-membered heteroaryl is preferably understood to mean a monovalent aromatic hydrocarbon ring system with 5 ring atoms, which contains at least 1 heteroatom, which may be identical or different, such a heteroatom being, for example, an oxygen, nitrogen or sulfur atom. In particular, the 5-membered heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl.

The term 6-membered heteroaryl is preferably understood to mean a monovalent aromatic hydrocarbon ring system with 6 ring atoms, which contains at least 1 heteroatom, which may be identical or different, and such a heteroatom can be, for example, an oxygen, nitrogen or sulfur atom. In particular, the 6-membered heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.

The term heteroaryl-C ₁ -C ₃ -alkyl preferably means heteroaryl, a 5-membered heteroaryl or 6-membered heteroaryl group, as defined above, where one of the hydrogen atoms is substituted by a C ₁ -C ₃ -alkyl group, as defined above, which connects a heteroaryl-C ₁ -C ₃ alkyl group with a molecule. In particular, heteroaryl-C ₁ -C ₃ -alkyl is heteroarylC ₁ -C ₂ -alkyl, pyridinyl-C ₁ -C ₃ -alkyl, pyridinylmethyl, pyridinylethyl, pyridinylpropyl, pyrimidinyl-C ₁ -C ₃ -alkyl, pyrimidinylmethyl, a pyrimidinyl ethyl, pyrimidinyl propyl, preferably pyridinyl methyl or pyridinyl ethyl or pyrimidinyl ethyl or pyrimidinyl propyl group.

When used in the text of this document, the term “leaving group” refers to an atom or group of atoms that are cleaved from the atom as a stable particle during the chemical reaction, carrying away the binding electron pair. Preferably, the leaving group is selected from the group consisting of halo, in particular chloro, bromo or iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutane-sulfonyloxy, (4-bromo-benzene) sulfonyloxy, (4-nitrobenzene) (2-sulfonyloxy, nitrobenzene) sulfonyloxy, (4-isopropylbenzene) sulfonyloxy, (2,4,6triisopropylbenzene) sulfonyloxy, (2,4,6-trimethylbenzene) sulfonyloxy, (4tertbutylbenzene) sulfonyloxy, benzene sulfonyloxy and (4-methoxybenzene) c.

The term C ₁ -C ₁₀ , when used throughout the text of this document, for example, in the context of the definition of C ₁ -C ₁₀ -alkyl, means an alkyl group with a certain number of carbon atoms: 1-10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. In addition, it should be understood that the specified term C ₁ -C ₁₀ should be interpreted as any subset contained in it, for example, C ₁ -C ₁₀ , C ₁ -C ₉ , C ₁ -C ₈ , C ₁ -C ₇ , C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ , C ₁ -C ₃ , C ₁ -C ₂ , C ₂ -C ₁₀ , C ₂ -C ₉ , C2-C8, C ₂ -C7 , C ₂ -C6, C ₂ -C5, C ₂ -C4, C2-C3, Се-Сш С3-С9, С3-С8, С3-С7, С3-С6, С3-С5, С3-С4, С4-С10 , С4-С9, С4С8, С4-С7, С4-С6, С4-С5, Сз-Сш С5-С9, С5-С8, С5-С7, С5-С6, С6-С10, С6-С9, С6-С8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, C8-C9, C9-C10.

Likewise, here, the term C ₃ -C _6, when used throughout this document, for example, in the context of determining a _C1-C6 alkyl, _C1-C6 alkoxy, it is understood an alkyl group of indicated number of carbon atoms: 1 -6 carbon atoms, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. In addition, it should be understood that the specified term C ₁ -C ₆ should be interpreted as any subset contained in it, for example, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2C6, C2- C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, C5-C6.

Likewise, here, the term C ₁ -C ₃ using the full text of the document, e.g., in the context of the definition _C1-C3 alkyl, _C1-C3 alkoxy or _C1-C3 -ftoralkoksi be understood alkyl group with a certain number of carbon atoms: 1-3 carbon atoms, i.e. 1, 2 or 3 carbon atoms. In addition, it should be understood that the term C1-C3 should be interpreted as any subset contained in it, for example, C1-C3, C1-C2, C2-C3.

In addition, here, under the term C3-C6, when used throughout the text of this document, for example, in the context of the definition of C3-C6 cycloalkyl, we should understand a cycloalkyl group with a certain number of carbon atoms: 3-6 carbon atoms, i.e. 3, 4, 5 or 6 carbon atoms. In addition, it should be understood that the specified term C ₃ -C ₆ should be interpreted as any subset contained in it, for example, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, C5-C6.

In addition, the term C ₃ -C ₇ , when used throughout the text of this document, for example, in the context of the definition of C ₃ -C ₇ -cycloalkyl, means a cycloalkyl group with a certain number of carbon atoms: 3-7 carbon atoms, t. e. 3, 4, 5, 6 or 7 carbon atoms, in particular 3, 4, 5 or 6 carbon atoms. In addition, it should be understood that the specified term C ₃ -C ₇ should be interpreted as any subset contained in it, for example, C3-C7, C3-C6, C3-C5, C3-C4, C4-C ₇ , C4-C6 , C4-C5, C5-C ₇ , C5-C6, C6-C ₇ .

The symbol / near the bond indicates the junction in the molecule.

As used herein, the term one or full, for example, in the definitions of substituents of the compounds of the general formula of the present invention, means one, two, three, four or five, more specifically one, two, three or four, even more specifically one, two or

- 12,027,226 three, more particularly one or two.

If the plural is used throughout this document: compounds, salts, hydrates, solvates and other similar terms, this also means the singular term: compound, salt, isomer, hydrate, solvate and other similar terms.

In accordance with another embodiment, the present invention relates to compounds of General formula (I), where

K ¹ represents a group selected from CgC ₆ -alkyl, Cz-C ₅ -cycloalkyl, wherein said group is optionally substituted with one substituent selected from the group of hydroxy, C ₁ -C ₃ -alkoxy, halo-C ₁ -C _2- alkyl, C ₁ -C _2- fluoroalkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, cyclic amines, -OR (O) (OH) ₂ , -C (O) OH, -C (O) X11 ₂ ;

K ² represents a group selected from

K ³ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy or halo-C ₁ -C ₃ -alkyl group;

K ⁴ represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom;

K ⁵ represents a group selected from a hydrogen atom, cyano, -C (O) K ⁹ , -C (O) OK ⁹ , -8 (O) 2K ⁹ , -C (O) XK ¹⁰ K ^p , -P ( O) (OK ¹² ) 2, -CH ₂ OR (OK ¹² ) ₂ , C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, heterocyclyl, phenyl, heteroaryl, where indicated C1-C6-alkyl, C3- The C7 cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, cyano, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy , -ΝΗ _2, alkylamino, dialkylamino, acetylamino, methyl-X-X-acetylamino, and cyclic ins, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ fluoroalkoxy;

K ⁶ , K ⁷ represent, independently of each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halo-C ₁ -C ₃ - alkyl, C ₁ -C ₃ fluoroalkoxy;

K ⁸ represents a group selected from:

a) C ₁ -C ₆ -alkyl group, which, if necessary, is substituted equally or differently by one, two, or three substituents selected from halogen, hydroxy, dialkylamino, acetylamino, X-methyl-X-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ -alkoxy, C ₃ -C ₇ -cycloalkyl, heterocyclyl, phenyl, heteroaryl wherein said C ₃ C ₇ cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, dialkylamino, acetylamino, X-methyl-X-acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ fluoroalkoxy;

b) a phenyl-C ₁ -C ₃ -alkyl group, in which the phenyl group is optionally substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy, dialkylamino, acetylamino, X-methyl -X-acetylamino, cyclic amines, cyano, C ₁ -C ₃ alkyl, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy;

c) a heteroaryl-C ₁ -C ₃ -alkyl group, in which, if necessary, the heteroaryl group is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy, dialkylamino, acetylamino, X-methyl -X-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy;

b) a C ₃ -C ₆ cycloalkyl-C ₁ -C ₃ alkyl group, a C ₃ -C ₆ cycloalkyl group in which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy;

f) a heterocyclyl-C ₁ -C ₃ -alkyl group, the heterocyclyl group of which, if necessary, is substituted equally or differently with one, two, or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy;

K ⁹ represents a group selected from C ₁ -C ₆ alkyl, halo-C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted , equally or differently, with one, two or three substituents selected from halogen, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -CH ₂ , alkylamino, dialkylamino, acetylamino, X-methyl-X- acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ C3-fluoroalkoxy;

K ¹⁰ , K ¹¹ represent, independently from each other, a group selected from hydrogen, C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, heterocyclyl, benzyl, phenyl or heteroaryl,

- 13 027226 wherein the C1-C ₆ alkyl, C ₃ -C ₇ -tsikloalkilBnaya, heterocyclyl, benzyl, phenyl or heteroaryl group, substituted by identical or different if necessary, one, two or three substituents selected from halogen, hydroxy , C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl- ^ acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ C3- fluoroalkoxy, or

K ¹⁰ and K ¹¹ together with the nitrogen atom to which they are attached form a cyclic amine;

K ¹² represents a group selected from hydrogen or C1-C4 alkyl, as well as to enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

In accordance with another embodiment, the present invention relates to compounds of General formula (I), where

K ¹ represents a group selected from C ₁ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, wherein said group is optionally substituted with one substituent selected from the group of hydroxy, C ₁ -C ₂ alkoxy, halo C ₁ -C ₂ -alkyl, C ₁ -C _2- fluoroalkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, cyclic amines, -OR (O) (OH) ₂ , -C (O) OH, -Ό (Ο) ΝΗ ₂ ;

K ² represents a group selected from

ABOUT'

K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a C ₁ -C ₃ alkyl group; K ⁴ represents a hydrogen atom or a fluorine atom;

wherein said C1-C6-alkyl, C3-C7-cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, X-methyl-X-acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ fluoroalkoxy;

K ⁶ , K ⁷ represent, independently of each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halo-C ₁ -C ₃ - alkyl, C ₁ -C ₃ fluoroalkoxy;

K ⁸ represents a group selected from:

a) C ₁ -C ₆ -alkyl group, which, if necessary, is substituted equally or differently by one, two, or three substituents selected from halogen, hydroxy, dialkylamino, acetylamino, X-methyl-X-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ -alkoxy, C ₃ -C ₇ -cycloalkyl, heterocyclyl, phenyl, heteroaryl wherein said C ₃ C7 cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents, selected from halogen, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, dialkylamino, acetylamino, метил-methyl-X-acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ - C ₃ fluoroalkoxy;

b) a phenyl-C ₁ -C ₃ -alkyl group, the phenyl group of which, if necessary, is substituted equally or differently with one, two, or three substituents selected from the group of halogen, hydroxy, dialkylamino, acetylamino, метил-methyl -X-acetylamino, cyclic amines, cyano, C ₁ -C ₃ alkyl, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy;

c) a heteroaryl-C ₁ -C ₃ -alkyl group, the heteroaryl group of which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy, dialkylamino, acetylamino, N-methyl -N-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy;

ά) a C ₃ -C ₆ cycloalkyl-C ₁ -C ₃ -alkyl group, a C ₃ -C ₆ -cycloalkyl group in which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy;

f) a heterocyclyl-C ₁ -C ₃ -alkyl group, the heterocyclyl group of which, if necessary, is substituted equally or differently with one, two, or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy;

K ⁹ represents a group selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted, the same or different, with one, two or three substituents selected from halogen, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ ₂ , alkyl-14,027,226 but, dialkylamino, acetylamino, X-methyl-X-acetylamino. cyclic amines, halo-C _g C ₃ -alkyl, C _g C ₃ -fluoroalkoxy;

K ¹⁰ , K ¹¹ represent, independently from each other, a group selected from hydrogen, CgC ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, benzyl, phenyl or heteroaryl, wherein said C ₁ -C _{6 is} alkyl, C _{The 3} -C ₇ cycloalkyl, heterocyclyl, benzyl, phenyl or heteroaryl group, if necessary, is substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ _2, alkylamino, dialkylamino, acetylamino, X-X-methyl-acetylamino, cyclic amines, halo-C ₁ -C ₃ alkyl C ₁ -C 3 fluoroalkoxy, or

K ¹⁰ and K ¹¹ together with the nitrogen atom to which they are attached form a cyclic amine; as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

In accordance with a preferred embodiment, the present invention relates to compounds of General formula (I), where

K ¹ represents a C ₁ -C ₆ alkyl or C ₃ -C ₅ cycloalkyl group, wherein said group is optionally substituted with one substituent selected from the group of hydroxy, C ₁ -C ₃ alkoxy, -ΝΗ ₂ , alkylamino , dialkylamino, cyclic amines, -OR (O) (OH) ₂ ;

K ² represents a group selected from

alkoxy or fluoro-C ₁ -C ₃ -alkyl group;

K ⁴ represents a hydrogen atom, a fluorine atom or a bromine atom;

K ⁵ represents a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —C (O) XK ¹⁰ K ¹¹ , —P (O) (OK ¹² ) 2, -SN2OR (PU ¹²⁾ 2, or C ₁ -C ₃ alkyl, wherein said C ₁ -C ₃ alkyl group optionally substituted with one substituent selected from -ΝΗ _2, alkylamino, dialkylamino or cyclic amines;

K ⁶ , K ⁷ represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom;

K ⁸ represents a group selected from:

a) a C ₁ -C ₃ -alkyl group, which, if necessary, is substituted equally or differently by one, two, or three substituents selected from halogen, halo-C ₁ -C ₃ -alkyl;

b) a phenyl-C ₁ -C ₃ -alkyl group, the phenyl group of which, if necessary, is substituted equally or differently with one, two, or three substituents selected from the group of halogen, cyano, C ₁ -C ₃ -alkyl , halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy;

c) a heteroaryl-C ₁ -C ₃ -alkyl group, the heteroaryl group of which, if necessary, is substituted with one or two substituents, equally or differently, selected from the group of halogen, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy;

K ⁹ represents a group selected from a C ₁ -C ₃ alkyl, halo-C ₁ -C ₃ alkyl or benzyl group, in which the phenyl group is optionally substituted with one or two substituents, equally or differently, selected from the group halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino;

K ¹⁰ , K ¹¹ represent, independently of one another, a group selected from hydrogen, C ₁ -C ₃ alkyl, benzyl, or

K ¹⁰ and K ¹¹ together with the nitrogen atom to which they are attached form a cyclic amine;

K ¹² represents a group selected from hydrogen or C ₁ -C ₂ alkyl, as well as to enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

In accordance with a preferred embodiment, the present invention relates to compounds of General formula (I), where

K ¹ represents a C ₁ -C ₆ alkyl or C ₃ -C ₅ cycloalkyl group, wherein said group is optionally substituted with one substituent selected from the group of hydroxy, C ₁ -C ₆ alkoxy, -ΝΗ ₂ , alkylamino , dialkylamino, cyclic amines, -OR (O) (OH) ₂ ;

K ² represents a group selected from

- 15 027226

K ⁴ represents a hydrogen atom or a fluorine atom;

K ⁵ represents a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —C (O) LK ¹⁰ K ¹¹ , —P (O) (OK) ₂ , - CH ₂ oR (OC) _2, or C _r C ₃ alkyl, wherein said _C1-C3 alkyl group optionally substituted with one substituent selected from -YN _2, alkylamino, dialkylamino or cyclic amines;

K ⁶ , K ⁷ represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom;

K ⁸ represents a group selected from:

a) a C ₁ -C ₃ -alkyl group, which, if necessary, is substituted equally or differently by one, two, or three substituents selected from halogen, halo-C ₁ -C ₃ -alkyl;

b) a phenyl-C ₁ -C ₃ -alkyl group, the phenyl group of which, if necessary, is substituted equally or differently with one, two, or three substituents selected from the group of halogen, cyano, C ₁ -C ₃ -alkyl , halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy;

c) a heteroaryl-C ₁ -C ₃ -alkyl group, the heteroaryl group of which, if necessary, is substituted with one or two substituents, equally or differently, selected from the group of halogen, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy;

K ⁹ represents a group selected from a C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or benzyl group, in which the phenyl group is optionally substituted with one or two substituents, equally or differently, selected from the halogen group, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -CH ₂ , alkylamino, dialkylamino;

K ¹⁰ , K ¹¹ represent, independently of one another, a group selected from hydrogen, C ₁ -C ₃ alkyl, benzyl, or

K ¹⁰ and K ¹¹ together with the nitrogen atom to which they are attached form a cyclic amine; as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

In accordance with another preferred embodiment, the present invention relates to compounds of General formula (I), where

K ¹ represents a C ₁ -C ₆ alkyl group, wherein said group is optionally substituted with one substituent selected from the group of hydroxy, C ₁ -C ₃ alkoxy, -CH ₂ , alkylamino, dialkylamino or cyclic amines;

K ² represents a group selected from

fluoromethyl or trifluoromethyl groups;

K ⁴ represents a hydrogen atom or a bromine atom;

K ⁵ represents a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —C (O) LK ¹⁰ K ¹¹ ;

K ⁶ , K ⁷ represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom;

K ⁸ represents a C ₁ -C ₃ alkyl group;

K ⁹ represents a C ₁ -C ₃ alkyl group, a benzyl group or trifluoromethyl;

K ¹⁰ , K ¹¹ represent, independently of each other, a group selected from hydrogen, C ₁ -C ₂ alkyl;

as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

In accordance with another preferred embodiment, the present invention relates to compounds of General formula (I), where

K ¹ represents a C ₁ -C ₆ alkyl group,

- 16 027226 where the specified group, if necessary, is substituted by one substituent selected from the group C ₁ -C ₃ alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino or cyclic amines;

K ² represents a group selected from

K ⁴ represents a hydrogen atom or a fluorine atom;

K ⁵ represents a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —C (O) NK ¹⁰ K ¹¹ ;

K ⁶ , K ⁷ represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom;

K ⁸ represents a C ₁ -C ₃ alkyl group;

K ⁹ represents a C ₁ -C ₃ alkyl group, a benzyl group or trifluoromethyl;

K ¹⁰ , K ¹¹ represent, independently of each other, a group selected from hydrogen, C ₁ -C ₂ alkyl;

as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

According to a particularly preferred embodiment, the present invention relates to compounds of the general formula (I), wherein

K ¹ represents a C ₁ -C ₃ alkyl group, wherein said group is optionally substituted with one substituent selected from the hydroxy group, -ΝΗ ₂ ;

K ² represents a group

K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a methyl, methoxy, difluoromethyl or trifluoromethyl group;

K ⁴ represents a hydrogen atom or a bromine atom;

K ⁵ represents a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —C (O) NK ¹⁰ K ¹¹ ;

K ⁶ represents a fluorine atom;

K ⁷ represents hydrogen;

K ⁸ represents a methyl or ethyl group;

K ⁹ represents methyl, ethyl or trifluoromethyl groups;

K ¹⁰ , K ¹¹ represent, independently of each other, a group selected from hydrogen, C ₁ -C ₂ alkyl;

as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

According to a particularly preferred embodiment, the present invention relates to compounds of the general formula (I), wherein

K ¹ represents a C ₁ -C ₃ alkyl group;

K ² represents a group

K ³ represents a hydrogen atom or a chlorine atom;

K ⁴ represents a hydrogen atom;

K ⁵ represents a group selected from a hydrogen atom, —C (O) K ⁹ ;

- 17 027226

K ⁶ represents hydrogen, parafluoro or parachloro, where the pair refers to the point where K ² joins the rest of the molecule;

K ⁷ represents hydrogen;

K ⁸ represents a methyl group;

K ⁹ represents a trifluoromethyl group;

as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

In accordance with another particularly preferred embodiment, the present invention relates to compounds of General formula (I), where

K ¹ represents a methyl, ethyl, 2-hydroxyethyl or 2-aminoethyl group;

K ² represents a 4-fluoro-2-methoxyphenyl or 4-fluoro-2-ethoxyphenyl group;

K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a methyl, methoxy, difluoromethyl or trifluoromethyl group;

K ⁴ represents a hydrogen atom or a bromine atom;

K ⁵ represents a hydrogen atom or a group selected from cyano, —C (O) CH ₃ , —C (O) CP ₃ , —C (O) OC ₂ H, —C (O) 0H) C ₂ H ₅ ;

as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

In accordance with another particularly preferred embodiment, the present invention relates to compounds of General formula (I), where

K ¹ represents a methyl group;

K ² represents a 4-fluoro-2-methoxyphenyl group;

K ³ represents a hydrogen atom or a chlorine atom;

K ⁴ represents a hydrogen atom;

K ⁵ represents a hydrogen atom;

as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

In accordance with still another embodiment of the invention relates to compounds of formula (I), where R ¹ represents a group selected from C1-C ₆ alkyl, C ₃ -C ₇ -cycloalkyl, heterocyclyl, phenyl, heteroaryl, phenyl-C1 C ₃ -alkyl- or heteroaryl-C 1 -C ₃ -alkyl, wherein said group is optionally substituted, equally or differently, with one, two, or three substituents selected from the group of hydroxy, cyano, halogen, halo-C1- C ₃ -alkyl, C ₄ -C ₆ alkoxy, C ₁ -C _3- fluoroalkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, ^ methyl- ^ acetylamino, cy of amine amines, —OR (O) (OH) ₂ , —C (O) OH, —C (O) XN ₂ .

According to another embodiment, the invention relates to compounds of formula (I), wherein K ¹ is a C ₄ -C ₃ alkyl, C ₃ -C ₅ cycloalkyl, 4-7 membered heterocyclic ring, phenyl, heteroaryl, phenyl -O-C ₂ -alkyl or heteroaryl-C1-C ₂ -alkyl group, where the specified group, if necessary, is substituted, the same or different, with one, two, or three substituents selected from the group of hydroxy, cyano, halogen, halo -C ₁ -C ₂ -alkyl, C ₁ -C ₃ alkoxy, C ₁ -C _2- fluoroalkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetamide Lamino, ^ methyl- ^ acetylamino, cyclic amines.

In accordance with still another embodiment of the invention relates to compounds of formula (I), where R ¹ represents a group selected from C1-C ₆ alkyl, C ₃ -C ₅ -cycloalkyl, wherein said group is substituted with one substituent if necessary selected from the group of hydroxy, _{C1-C2-alkoxy, halo-C1-C2-alkyl, C1-C2} -ftoralkoksi, -ΝΗ _2, alkylamino, dialkylamino, cyclic amines, -OP (O) (OH) _2, -C (O) OH, -C (O) YAN ₂ .

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ¹ is a group selected from C ₄ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, wherein said group is optionally substituted with one a substituent selected from the group of hydroxy, C | -C ₃ -alkoxy, halo-C ₄ -C ₂ -alkyl, C ₄ -C _2- fluoroalkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, cyclic amines, -OR (O) ( OH) ₂ , -C (O) OH, -C (O) YAN ₂ .

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ¹ represents a phenyl or heteroaryl group, wherein said group is optionally substituted, equally or differently, with one, two, or three substituents selected from groups of hydroxy, cyano, halogen, halo-C ₁ -C ₂ -alkyl, C ₄ -C ₃ alkoxy, C ₁ -C _2- fluoroalkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl- ^ acetylamino, cyclic amines.

In accordance with still another embodiment of the invention relates to compounds of general formula (I), where R ¹ represents a group selected from C1-C ₆ alkyl, C ₃ -C ₅ -cycloalkyl, wherein said group optionally substituted with one or two substituents, the same or different, selected from hydroxy groups, C ₁ -C ₂ -alkoxy, _{halo-C1-C2-alkyl,} C ₁ -C ₂ -ftoralkoksi,

- 18 027226

-YN2, -OR (O) (OH) 2, -C (O) OH, -C (O) ON2.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ¹ is a group selected from methyl, ethyl, propan-2-yl, tert-butyl, cyclopropyl, cyclohexyl or phenyl, wherein said group, when optionally substituted with one substituent selected from the group of hydroxy or methoxy.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ¹ is a group selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or phenylC ₁ -C ₃ alkyl, where said group is optionally substituted, equally or differently, with one, two, or three substituents selected from the group of hydroxy or C ₁ -C ₆ alkoxy.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ¹ is a group selected from C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl or phenylC ₁ -C ₂ alkyl, where said group is optionally substituted, equally or differently, with one, two, or three substituents selected from the group hydroxy or C ₁ -C ₃ alkoxy.

According to a preferred embodiment, the present invention relates to compounds of the general formula (I), wherein K ¹ represents a C ₁ -C ₆ alkyl or C ₃ -C ₅ cycloalkyl group, wherein said group is optionally substituted with one substituent, selected from the group of hydroxy, C ₁ -C ₆ alkoxy, -CH ₂ , alkylamino, dialkylamino, cyclic amines, -OR (O) (OH) ₂ .

According to a preferred embodiment, the present invention relates to compounds of the general formula (I), wherein K ¹ represents a C ₁ -C ₆ alkyl or C ₃ -C ₅ cycloalkyl group, wherein said group is optionally substituted with one substituent, selected from the group of hydroxy, C ₁ -C ₃ alkoxy, -CH ₂ , alkylamino, dialkylamino, cyclic amines, -OR (O) (OH) ₂ .

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹ represents a C ₁ -C ₆ alkyl group, wherein said group is optionally substituted with one substituent selected from the hydroxy group, C ₁ - C ₆ -alkoxy, -TH ₂ , -OR (O) (OH) 2.

According to another preferred embodiment, the present invention relates to compounds of the general formula (I), wherein K ¹ represents a C ₁ -C ₆ alkyl group, wherein said group is optionally substituted with one substituent selected from the group C ₁ - C ₃ alkoxy, -CH ₂ , alkylamino, dialkylamino or cyclic amines.

According to another preferred embodiment, the present invention relates to compounds of the general formula (I), wherein K ¹ is a C ₁ -C ₆ alkyl group, wherein said group is optionally substituted with one substituent selected from the hydroxy group, C ₁ -C ₃ -alkoxy, -CH ₂ , alkylamino, dialkylamino or cyclic amines.

According to yet another preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹ is a group selected from methyl, ethyl, propan-2-yl, cyclopropyl, tert-butyl, cyclopentyl, cyclohexyl or phenyl, wherein the group is optionally substituted with one substituent selected from the group C ₁ -C ₃ alkoxy, -CH ₂ , alkylamino, dialkylamino or cyclic amines.

According to yet another preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹ is a group selected from methyl, ethyl, propan-2-yl, cyclopropyl or tert-butyl, wherein said group is optionally substituted one substituent selected from the group C ₁ -C ₃ alkoxy, -CH ₂ , alkylamino, dialkylamino or cyclic amines.

According to a preferred embodiment, the present invention relates to compounds of the general formula (I), wherein K ¹ represents a C ₁ -C ₆ alkyl group, wherein said group is optionally substituted with one substituent selected from the hydroxy group or —OR ( O) (OH) 2.

According to a particularly preferred embodiment, the present invention relates to compounds of the general formula (I), wherein K ¹ represents a C ₁ -C ₃ alkyl group.

According to a particularly preferred embodiment, the present invention relates to compounds of the general formula (I), wherein K ¹ represents a C ₁ -C ₃ alkyl group, wherein said group is optionally substituted with one substituent selected from the hydroxy group, —TH ₂ .

According to a particularly preferred embodiment, the present invention relates to compounds of the general formula (I), wherein K ¹ represents a methyl, ethyl, 2 hydroxyethyl or 2-aminoethyl group.

In accordance with another particularly preferred embodiment, the present invention relates to compounds of the general formula (I), wherein K ¹ represents a methyl group.

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ² represents a group selected from

- 19 027226

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ² represents a group selected from

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ² represents a group selected from

In accordance with a preferred embodiment, the invention relates to compounds of formula (I), where K ² represents a group selected from

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ² is

According to another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ² represents a 4-fluoro-2-methoxyphenyl group.

According to another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ² represents a 4-fluoro-2-methoxyphenyl or 4 fluoro-2-ethoxyphenyl group.

According to another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ² represents a 4-fluoro-2-ethoxyphenyl group.

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ³ and K ⁴ represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, cyano, C-Cz-alkyl, C-Cz-alkoxy, halo-C-Cz-alkyl, C ₁ -C ₃ fluoroalkoxy.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a C — C ₃ alkyl group, and K ⁴ represents a hydrogen atom or a fluorine atom.

In accordance with another preferred embodiment of the invention relates to compounds of formula (I), where R ³ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a _C1-C3 alkyl, _C1-C3 alkoxy or halo _C1-C3 alkyl group, and K ⁴ represent a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a C1C ₃ -alkyl, C1-C ₃ -alkoxy or fluoro-C1-C ₃ - an alkyl group, and K ⁴ represents a hydrogen atom, a fluorine atom or a bromine atom.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom, and K ⁴ represents a hydrogen atom or a fluorine atom.

According to another preferred embodiment, the invention relates to compounds of formula (I), where K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a methyl, methoxy, difluoromethyl or trifluoromethyl group, and K ⁴ represents a hydrogen atom or a bromine atom .

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a hydrogen atom or a chlorine atom, and K ⁴ represents a hydrogen atom.

In accordance with still another embodiment of the invention relates to compounds of formula (I), where R ³ represents a group selected from a hydrogen atom, a fluorine atom, chlorine atom, bromine atom, cyano, _C1-C3 alkyl, _C1-C3 alkoxy, _halo-C1-C3 alkyl, _C1-C3 -ftoralkoksi.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ³ is a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a C ₁ C ₃ alkyl, a C ₁ -C ₃ alkoxy, halo _C1-C3 alkyl, _C1-C3 -ftoralkoksi.

In accordance with yet another embodiment, the invention relates to compounds of formula (I), wherein K ³ is a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a C ₁ -C ₂ alkyl, a C 1 -C ₂ alkoxy, halo-C 1- C ₂ -alkyl, C 1 -C ₂ fluoroalkoxy.

In accordance with another preferred embodiment of the invention relates to compounds of formula (I), where R ³ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a _C1-C3 alkyl, _C1-C3 alkoxy or halo _C1-C3 alkyl group.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a C — C ₃ alkyl group.

In accordance with another preferred embodiment of the invention relates to compounds of formula (I), where R ³ represents a _C1-C3 alkyl, _C1-C3 alkoxy or _halo-C1-C3 alkyl group.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ³ represents a C-C ₃ -alkyl group.

According to another preferred embodiment, the invention relates to compounds of the formula (I), wherein K ³ represents a group selected from a hydrogen atom, a fluorine atom or a chlorine atom.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a C1C ₃ -alkyl, C1-C ₃ -alkoxy or fluoro-C1-C ₃ - an alkyl group.

In accordance with another preferred embodiment of the invention relates to compounds of formula (I), where R ³ represents a hydrogen atom or a _C1-C3 alkyl, _C1-C3 alkoxy or _fluoro-C1-C3 alkyl group.

In accordance with another preferred embodiment of the invention relates to compounds of formula (I), where R ³ represents a hydrogen atom or a _C1-C3 alkyl or fluoro-alkyl group DS3.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a hydrogen atom or a C1-C ₃ alkyl group.

In accordance with another preferred embodiment of the invention relates to compounds of formula (I), where R ³ represents a hydrogen atom or a fluoro _C1-C3 alkyl group.

In accordance with another preferred embodiment of the invention relates to compounds of formula (I), where R ³ represents a _C1-C3 alkyl, _C1-C3 alkoxy or _fluoro-C1-C3 alkyl group.

- 21 027226

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ³ represents a fluorine-C3-alkyl group.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a methyl, methoxy, difluoromethyl or trifluoromethyl group.

According to yet another preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents methyl, methoxy, difluoromethyl or trifluoromethyl groups.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a difluoromethyl or trifluoromethyl group.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ³ represents a methyl group.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ³ represents a methoxy group.

According to yet another preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a trifluoromethyl group.

According to yet another preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a difluoromethyl group.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ³ represents a fluorine atom or a chlorine atom.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a hydrogen atom or a fluorine atom.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ³ represents a fluorine atom.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a hydrogen atom or a chlorine atom.

In accordance with another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a hydrogen atom.

In accordance with another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ³ represents a chlorine atom.

In accordance with still another embodiment of the invention relates to compounds of formula (I), where R ⁴ represents a group selected from a hydrogen atom, a fluorine atom, chlorine atom, bromine atom, cyano, _C1-C3 alkyl, _C1-C3 alkoxy, _halo-C1-C3 alkyl, _C1-C3 -ftoralkoksi.

In accordance with yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁴ is a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C) C ₃ alkyl, C 1 -C ₃ alkoxy, halo _C1-C3 alkyl, _C1-C3 -ftoralkoksi.

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ⁴ represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C ₁ C ₂ -alkyl, C ₁ -C ₂ -alkoxy, halo -C ₁ -C ₂ -alkyl; C ₁ -C _2- fluoroalkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁴ represents a group selected from a hydrogen atom, fluorine atom or a chlorine atom.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁴ represents a fluorine atom or a chlorine atom.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁴ is a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁴ is a group selected from a hydrogen atom, a fluorine atom or a bromine atom.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁴ represents a bromine atom.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁴ represents a group selected from a hydrogen atom or a fluorine atom.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁴ represents a group selected from a hydrogen atom or a bromine atom.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁴ represents a fluorine atom.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁴ represents a hydrogen atom.

In accordance with yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) Ok ⁹ ,

-8 (O) ₂ K ⁹ , ^^ ΝΕ ¹⁰ ^ ¹ , -P (O) (OK) ₂ , -CH ₂ OP (OK) ₂ , C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl , heterocyclyl, phenyl, heteroaryl, wherein said C ₁ -C ₆ -alkyl, Cz-C ₇ -cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl-Y-acetylamino, cyclic amines, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy.

In accordance with another embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , -8 (O ) 2К ⁹ , -С (О) ЯК ¹⁰ К ¹¹ , -Р (О) (ОК ¹² ) 2, -ССОР (ОК ¹² ) ₂ , С ₁ -С ₆ -alkyl, С ₃ -С ₇ -cycloalkyl, heterocyclyl , phenyl, heteroaryl, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, cyano, C1-C3- alkyl, C1-C3 alkoxy, -ΝΗ2, alkylamino, dialkylamino, acetylamino, OTmethyl-I-acetylamino, cyclic amines, halo-C ₁ -C ₃ alkyl, C1-C3 fluoroalkoxy.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —C (O) YAK ¹⁰ K ¹¹ , —P (O) (OK) ₂ , —SCHOR (OK) _2, or C ₁ -C ₃ -alkyl, wherein said C ₁ -C ₃ -alkyl group is optionally substituted with one substituent selected from -ΝΗ ₂ , alkylamino, dialkylamino or cyclic amines.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —C ( O) \ N N. —P (O) (OK ¹² ) 2, -SCHOR (OK ¹² ) 2 or C1-C ₃ -alkyl, wherein said 0-C ₃ alkyl group is optionally substituted with one substituent selected from -ΝΗ2, alkylamino, dialkylamino or cyclic amines.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , -8 ( O) 2K ⁹ , -C (O) \ KK. -P (O) (OK) 2, -SCHOR (OK) ₂ , methyl.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , -8 ( O) 2K ⁹ , - ('(Okin. -P (O) (OK ¹² ) 2, -SCHOR (OK ¹² ) 2, methyl.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁵ represents a group selected from cyano, -C (O) K ⁹ , -C (O) OK ⁹ , -8 (O) 2K ⁹ , -C (O) \ QC. -P (O) (OK) 2, -SCHOR (OK) 2, methyl.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁵ represents a group selected from cyano, -C (O) K ⁹ , -C (O) OK ⁹ , -8 (O) 2K ⁹ , -C (O) \ QC. -P (O) (OK ¹² ) 2, -SCHOR (OK ¹² ) 2, methyl.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁵ represents a group selected from cyano, -8 (O) 2K ⁹ , -C (OAC ¹⁰ K11, -P (O) (OK) ) 2, -SCHOR (OK) ₂ .

In accordance with yet another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from cyano, -8 (O) 2K ⁹ , -HNF ^ K ¹¹ , -P (O) (OK ¹² ) 2, -SCHOR (OK ¹² ) ₂ .

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —POLK K.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from cyano, —C (O) OK ⁹ , —HNF ^ K ¹¹ .

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from cyano or —C (O) OK ⁹

In accordance with another embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from a hydrogen atom or a cyano group.

In accordance with another embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from a hydrogen atom or —C (O) OK ⁹ .

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is —C (O) OK ⁹

In accordance with yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is —HANDLER ^ K ¹¹ .

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁵ represents a cyano group.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from a hydrogen atom or —C (O) K ⁹

In accordance with another particularly preferred embodiment, the invention

- 23,027,226 relates to compounds of formula (I), wherein K ⁵ is —C (O) K ⁹ .

In accordance with another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ represents a hydrogen atom.

According to another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ represents a hydrogen atom or a group selected from cyano, —C (O) CH ₃ , —C (O) CP ₃ , —C (О) OS ₂ Н ₅ , -С (ОЖН) С ₂ Н ₅ .

According to another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ represents a hydrogen atom or a group selected from —C (O) CH ₃ or —C (O) CP ₃ .

According to another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁵ is a group selected from —C (O) CH ₃ or —C (O) CP ₃ .

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ⁶ , K ⁷ represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C ₁ -C ₃ -alkyl , C ₁ -C ₃ alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁶ and K ⁷ are, independently from each other, a group selected from a hydrogen atom or a fluorine atom or C ₁ -C ₃ alkoxy.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁶ and K ⁷ represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom.

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ⁶ and K ⁷ represent, independently from each other, a group selected from a hydrogen atom or a fluorine atom.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁶ is hydrogen, parafluoro or parachloro, where steam is at the point where K ^{2 is} attached to the rest of the molecule and where K ⁷ is a hydrogen atom.

In accordance with another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁶ is a paraffluoro, where steam refers to the point where K ^{2 is} attached to the rest of the molecule and where K ⁷ is a hydrogen atom.

According to another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁶ represents a fluorine atom and where K ⁷ represents a hydrogen atom.

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ⁶ represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C ₁ C ₃ alkyl, C ₁ -C ₃ alkoxy, halo -C ₁ -C ₃ -alkyl; C ₁ -C _3- fluoroalkoxy.

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ⁶ represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C ₁ C ₂ -alkyl, C ₁ -C ₂ -alkoxy, halo -C ₁ -C ₂ -alkyl; C ₁ -C _2- fluoroalkoxy.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁶ is a group selected from a hydrogen atom, a fluorine atom, a chlorine atom.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁶ represents a hydrogen atom.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁶ represents a fluorine atom.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁶ represents a chlorine atom.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁶ is hydrogen, parafluoro or parachloro, where steam refers to the point where K ^{2 is} attached to the rest of the molecule.

In accordance with another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁶ is a paraffluoro, where steam refers to the point where K ^{2 is} attached to the rest of the molecule.

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ⁷ represents a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C ₁ C ₃ alkyl, C ₁ -C ₃ alkoxy, halo -C ₁ -C ₃ -alkyl; C ₁ -C _3- fluoroalkoxy.

In accordance with yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁷ is a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a C ₁ C ₂ alkyl, C ₁ -C ₂ alkoxy, halo -C ₁ -C ₂ -alkyl; C ₁ -C _2- fluoroalkoxy.

In accordance with a preferred embodiment, the invention relates to compounds of formula (I), where K ⁷ represents a group selected from a hydrogen atom, a fluorine atom, an atom

- 24,027,226 chlorine.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁷ represents a fluorine atom.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁷ represents a chlorine atom.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁷ represents a hydrogen atom.

In accordance with still another embodiment of the invention relates to compounds of formula (I), where R ⁸ represents a _C1-C6 alkyl group, which optionally substituted identically or differently, one or two, or three substituents selected from halogen, hydroxy, -YN _2, alkylamino, dialkylamino, acetylamino, Ν-methyl-N-acetylamino, cyclic amines, cyano, _{C1-C3-alkyl, halo-C1-C3} alkyl, _C1-C3 -ftoralkoksi , C1-C ₃ alkoxy, C ₂ -C ₃ -alkenyl, C ₂ -C ₃ -alkynyl, C3 -C7 cycloalkyl, heterocyclyl, phenyl, heteroaryl, wherein said 3-C7-cycloalkyl, heterocyclyl, phenyl or heteroaryl group optionally substituted with identically or differently one, two or three substituents selected from halo, hydroxy, _C1-C3 alkyl, _C1-C3 alkoxy, - NH _2, alkylamino, dialkylamino, acetylamino, Ν-methyl-N-acetylamino, cyclic amines, _halo-C1-C3 alkyl, _C1-C3 -ftoralkoksi.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a C ₁ -C ₆ alkyl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents, selected from halogen, hydroxy, dialkylamino, acetylamino, метил-methyl-Y-acetylamino, cyclic amines, cyano, C ₁ -C ₃ alkyl, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, C C ₁ -C ₃ alkoxy, C ₃ -C ₇ -cycloalkyl, heterocyclyl, phenyl, heteroaryl, wherein said C3-C7 cycloalkyl, heterocyclyl, hair a linear or heteroaryl group, if necessary, is substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, dialkylamino, acetylamino, Y-methyl-Y-acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy.

In accordance with yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a C ₁ -C ₃ alkyl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents, selected from halogen, hydroxy, —YN ₂ , alkylamino, dialkylamino, acetylamino, Y-methyl-Y-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ - C ₃ fluoroalkoxy, C ₁ -C ₃ alkoxy, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, C3-C7 cycloalkyl, heterocyclyl, phenyl, heteroaryl, where indicated This C3-C7 cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, -CH2, alkylamino , dialkylamino, acetylamino, Y-methyl-Y-acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a C ₁ -C ₆ alkyl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents, selected from the group of a halogen atom, C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocyclyl, phenyl, heteroaryl, wherein said C ₃ C ₆ cycloalkyl, C ₃ -C ₆ heterocyclyl , a phenyl or heteroaryl group is optionally substituted with one substituent selected from halogen.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a C ₁ -C ₃ alkyl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from halogen, halo-C ₁ -C ₃ -alkyl.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁸ represents a C ₁ -C ₃ -alkyl group.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁸ represents a group selected from methyl, ( ² H ₃ ) methyl.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a methyl group.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a methyl or ethyl group.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents an ethyl group.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a C3-C7 cycloalkyl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from halogen, hydroxy, -CH2, alkylamino, dialkylamino, acetylamino, Y-methyl-Y-acetylamino, cyclic amines, cyano, C ₁ -C ₃ alkyl, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ -fluoroalkoxy, C ₁ -C ₃ alkoxy, C ₂ -C ₃ alkenyl, C ₂ C3 alkynyl.

- 25 027226

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a cyclopentyl or cyclohexyl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the fluorine group , chloro, hydroxy, -ΝΗ _2, alkylamino, dialkylamino, acetylamino, K-methyl-Katsetilamino, cyclic amines, cyano, _{C1-C2-alkyl, halo-C1-C2-alkyl, C1-C2} -ftoralkoksi, C -C ₂ alkoxy, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a heterocyclyl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy , -ΝΗ _2, alkylamino, dialkylamino, acetylamino, N-methyl-I-acetylamino, cyclic amines, cyano, _{C1-C3-alkyl, halo-C1-C3} alkyl, _C1-C3 -ftoralkoksi, C1-C _3- alkoxy, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl.

In accordance with yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a 4-7 membered heterocyclic ring which is optionally substituted with one, or two, or three substituents, equally or differently, selected from group consisting of halogen, hydroxy, -ΝΗ _2, alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, cyano, _{C1-C3-alkyl, halo-C1-C3} alkyl, _C1-C3 -ftoralkoksi , C1-C ₃ alkoxy, C ₂ -C ₃ -alkenyl, C ₂ -C ₃ -alkynyl.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a phenyl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy , -ΝΗ _2, alkylamino, dialkylamino, acetylamino, N-methyl-I-acetylamino, cyclic amines, cyano, _{C1-C3-alkyl, halo-C1-C3} alkyl, _C1-C3 -ftoralkoksi, C1-C _3- alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a phenyl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy , -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, M-methyl-I-acetylamino, cyclic amines, cyano, C ₁ -C ₂ alkyl, halo-C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkoxy, C ₁ -C ₂ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a phenyl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, dialkylamino , cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a heteroaryl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy , -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, M-methyl-I-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a heteroaryl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, hydroxy , -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, M-methyl-I-acetylamino, cyclic amines, cyano, C ₁ -C ₂ alkyl, halo-C ₁ -C ₂ alkyl, C ₁ -C ₂ fluoroalkoxy, C ₁ -C ₂ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a heteroaryl group which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the group of halogen, dialkylamino , cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a phenyl-C ₁ -C ₃ -alkyl group, in which the phenyl group is optionally substituted, equally or differently, with one or two , or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl-а acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ fluoroalkoxy; C ₁ -C ₃ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a phenyl-C ₁ -C ₂ -alkyl group, in which the phenyl group is optionally substituted, equally or differently, with one or two or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, M-methyl-цет acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl C ₁ -C ₃ fluoroalkoxy; C ₁ -C ₃ alkoxy.

In accordance with another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a phenyl-C ₁ -C ₂ -alkyl group, in which, at

- 26 027226 necessary, substituted, equally or differently, by one, two, or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, N-methyl-Nacetylamino, cyclic amines, cyano, C ₁ -C ₂ -alkyl, halo-C ₁ -C ₂ -alkyl, C ₁ -C _2- fluoroalkoxy, C ₁ -C ₂ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a benzyl group, the phenyl group of which, if necessary, is substituted, equally or differently, with one, two, or three substituents selected from the group halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, cyano, C ₁ -C ₂ -alkyl, halo-C ₁ -C ₂ -alkyl, C ₁ -C ₂ -fluoroalkoxy; C ₁ -C ₂ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a phenyl-C ₁ -C ₃ -alkyl group, in which the phenyl group is optionally substituted, equally or differently, with one or two , or three substituents selected from the group of halogen, hydroxy, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ - C ₃ fluoroalkoxy; C ₁ -C ₃ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a phenyl-C ₁ -C ₃ -alkyl group, in which the phenyl group is optionally substituted, equally or differently, with one or two or three substituents selected from the group of halogen, hydroxy, cyano, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a phenyl-C ₁ -C ₃ -alkyl group, in which the phenyl group is optionally substituted with one, two, or three substituents equally or differently selected from the group of halogen, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy, C ₁ -C ₃ -alkoxy.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a phenyl-C ₁ -C ₃ -alkyl group, in which the phenyl group is optionally substituted, equally or differently, with one, or two or three substituents selected from the group of halogen or C ₁ -C ₃ alkoxy.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁸ represents a phenyl-C ₁ -C ₃ -alkyl group.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a phenyl-C ₁ -C ₂ -alkyl group, in which the phenyl group is optionally substituted, equally or differently, with one, or two or three substituents selected from the group of halogen or C1-C3 alkoxy.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁸ represents a phenyl-C ₁ -C ₂ -alkyl group.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁸ represents a benzyl group, in which the phenyl group is optionally substituted, equally or differently, with one, two, or three substituents selected from halogen groups or C ₁ -C ₃ alkoxy.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁸ represents a benzyl group.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a heteroaryl-C ₁ -C ₃ -alkyl group, in which the heteroaryl group is optionally substituted, equally or differently, with one or two or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, methyl-Y-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl C ₁ -C ₃ fluoroalkoxy; C ₁ -C ₃ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a heteroaryl-C ₁ -C ₃ -alkyl group, in which the heteroaryl group is optionally substituted, equally or differently, with one or two , or three substituents selected from the group of halogen, hydroxy, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, cyano, C ₁ -C ₃ -alkyl, halo-C ₁ -C ₃ -alkyl, C ₁ - C ₃ fluoroalkoxy; C ₁ -C ₃ alkoxy.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a heteroaryl-C ₁ -C ₂ -alkyl group, in which the heteroaryl group is optionally substituted, the same or different, with one or two or three substituents selected from the group of halogen, hydroxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, Ν methyl-H-acetylamino, cyclic amines, cyano, C ₁ -C ₃ alkyl, halo-C ₁ -C ₃ alkyl C ₁ -C ₃ fluoroalkoxy; C ₁ -C ₃ alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a pyridyl-C ₁ -C ₂ alkyl group, in which the pyridyl group is optionally substituted, the same or different, with one or two , or three substituents,

- 27 027226 selected from the group consisting of halogen, hydroxy, -ΝΗ _2, alkylamino, dialkylamino, acetylamino, №metil-№ acetylamino, cyclic amines, cyano, _{C1-C2-alkyl, halo-C1-C2-alkyl,} C1-C ₂ -fluoroalkoxy, C1-C2 alkoxy.

In accordance with a preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a heteroaryl-C-C3-alkyl group, in which the heteroaryl group is optionally substituted with one or two substituents, the same or different, selected from the group halogen, cyano, _{C1-C3-alkyl, halo-C1-C3} alkyl, _C1-C3 -ftoralkoksi, _Ci-3 alkoxy.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁸ represents a pyridyl-C1-C ₃ -alkyl group, in which the pyridyl group, if necessary, is substituted, the same or different, one or two or three substituents selected from the group of halogen or C1-C3 alkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a pyridyl-CH ₂ group, in which the pyridyl group is optionally substituted, equally or differently, with one, two, or three substituents selected from the group consisting of halogen, _{C1-C2-alkyl, halo-C1-C2-alkyl, -C1-C2} -ftoralkoksi, _C1-C2 alkoxy.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a pyridyl-CH ₂ group, in which the pyridyl group is optionally substituted with one or two substituents, equally or differently, selected from the group halogen or C ₁ -C ₃ alkoxy.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ represents a C ₃ -C ₆ cycloalkyl-C ₁ -C ₃ alkyl group, a C ₃ -C ₆ cycloalkyl group in which, if necessary, substituted, equally or differently, by one, two, or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ - With ₃ fluoroalkoxy.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a C ₃ -C ₆ cycloalkyl-CH ₂ group, a C ₃ -C ₆ cycloalkyl group in which, if necessary, is substituted, the same or different, one, or two, or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy .

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a cyclohexyl-CH ₂ - or cyclopentyl-CH ₂ - group, the cyclohexyl or cyclopentyl group of which, if necessary, is substituted, the same or different, one, or two, or three substituents selected from fluorine, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, trifluoromethyl, C1-C3-fluoroalkoxy.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a heterocyclyl-C ₁ -C ₃ -alkyl group, in which the heterocyclyl group is optionally substituted, the same or different, with one or two or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy.

In accordance with yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁸ is a heterocyclyl-CH ₂ group, the heterocyclyl group of which, if necessary, is substituted equally or differently with one, two, or three substituents selected from halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁹ is a group selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, where said group, if necessary, is substituted, equally or differently, by one, two or three substituents selected from halogen, hydroxy, C1-C3-alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, ^ methyl ^ acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ⁹ is a group selected from C ₁ -C ₆ alkyl, halo-C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, -ΝΗ _2, alkylamino, dialkylamino, acetylamino, №metil-№ acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -fluoroalkyl si.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ⁹ is a group selected from C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, where said group, if necessary, is substituted, equally or differently, by one, two or three substituents selected from halogen, hydroxy, C1-C3-alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, ^ methyl ^ acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy.

In accordance with a preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁹ represents a group selected from a C ₁ -C ₃ alkyl, halo-C ₁ -C ₃ - 28 027226 alkyl or benzyl group, a phenyl group in which, if appropriate, substituted with one or two substituents, the same or different, selected from the group halogen, C1-C3 alkyl, C1C ₃ -alkoxy, -ΝΗ _2, alkylamino, dialkylamino.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁹ is a group selected from a C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, benzyl group, in which a phenyl group, if necessary, substituted by one or two substituents, equally or differently, selected from the group of halogen, C ₁ -C ₃ -alkyl, C ₁ C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁹ is a group selected from C ₁ -C ₆ alkyl.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁹ is a group selected from C ₁ -C ₃ alkyl, which is optionally substituted with C ₁ -C ₃ alkoxy.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁹ is a group selected from C ₁ -C ₃ alkyl, benzyl or trifluoromethyl.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ⁹ represents a C ₁ -C ₃ -alkyl group.

In accordance with another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁹ represents methyl, ethyl or trifluoromethyl groups.

In accordance with another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁹ represents a trifluoromethyl group.

In accordance with another particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ⁹ represents a methyl group.

In accordance with another particularly preferred embodiment, the invention relates to compounds of formula (I), where K ⁹ represents an ethyl group.

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ¹⁰ , K ¹¹ represent, independently from each other, a group selected from hydrogen, C ₁ C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl , heterocyclyl, phenyl, benzyl or heteroaryl, wherein said C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, - ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, halo-C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkoxy, or K ¹⁰ and K ¹¹ together with a nitrogen atom, to which they are attached form a cyclic amine.

In accordance with another embodiment, the invention relates to compounds of formula (I), where K ¹⁰ and K ¹¹ represent, independently from each other, a group selected from hydrogen, C ₁ -C ₅ alkyl, C ₃ -C ₆ - cycloalkyl, heterocyclyl, phenyl or heteroaryl, wherein said C ₁ -C ₅ alkyl, C ₃ -C ₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ _2, alkylamino, di lkilamino, acetylamino, Νmetil-N-acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C ₃ -ftoralkoksi.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹⁰ and K ¹¹ are, independently from each other, a group selected from hydrogen, C1-C3 alkyl, benzyl, or K ¹⁰ and K ¹¹ together with the nitrogen atom to which they are attached form a cyclic amine.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ¹⁰ and K ¹¹ represent, independently from each other, a group selected from hydrogen or C ₁ -C ₂ -alkyl.

According to yet another preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹⁰ and K ¹¹ are, independently of one another, hydrogen or C ₁ C 6 -alkyl.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹⁰ and K ¹¹ are hydrogen.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ¹⁰ is a group selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl wherein said C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C1C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹⁰ represents a group selected from hydrogen, C ₁ -C ₃ alkyl, benzyl.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹⁰ is a group selected from hydrogen, C ₁ -C ₆ alkyl.

According to another preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹⁰ is a group selected from hydrogen or C ₁ -C ₂ alkyl.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹⁰ is C ₁ -C ₂ alkyl.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹⁰ is hydrogen.

According to yet another embodiment, the invention relates to compounds of formula (I), wherein K ¹¹ is a group selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl wherein said C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl group is optionally substituted, equally or differently, with one, two or three substituents selected from halogen, hydroxy, C1C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -ΝΗ ₂ , alkylamino, dialkylamino, acetylamino, N-methyl-N-acetylamino, cyclic amines, halo-C ₁ -C ₃ -alkyl, C ₁ -C _3- fluoroalkoxy.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹¹ is a group selected from hydrogen, C ₁ -C ₃ alkyl, benzyl.

According to yet another preferred embodiment, the invention relates to compounds of formula (I), wherein K represents a group selected from hydrogen, C ₁ -C ₆ alkyl.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ¹¹ represents a group selected from hydrogen or C ₁ -C ₂ -alkyl.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ¹¹ represents a C ₁ -C ₂ -alkyl.

According to a particularly preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹¹ is hydrogen.

According to another embodiment, the invention relates to compounds of formula (I), wherein K ¹² is a group selected from hydrogen, C ₁ -C ₄ alkyl or benzyl.

According to a preferred embodiment, the invention relates to compounds of formula (I), wherein K ¹² is a group selected from hydrogen or C ₁ -C ₄ alkyl.

In accordance with another preferred embodiment, the invention relates to compounds of formula (I), where K ¹² represents a group selected from hydrogen or C ₁ -C ₂ -alkyl.

It should be understood that the present invention also relates to any subcombination within any of the embodiments of the present invention with respect to compounds of the general formula (I) described above.

In accordance with another preferred embodiment, the invention relates to a specific stereoisomer of compounds of formula (I) with a lower Κ. ' ₅₀ in relation to ί'.ΌΙ <9 in comparison with other stereoisomers of the corresponding compound, which is determined by method 1a described in the Materials and methods section below.

In accordance with another preferred embodiment, the invention relates to a specific stereoisomer of compounds of formula (I) with a lower Κ. ' ₅₀ with respect to ί'.ΌΙ <9 at high ATP concentrations compared to other stereoisomers of the corresponding compound, which is determined by method 1b described in the Materials and methods section below.

In accordance with another preferred embodiment, the invention relates to a specific stereoisomer of the compounds of formula (I) with higher selectivity to ί'.ΌΙ <9 relative to ί'.ΌΙ <2 compared to other stereoisomers of the corresponding compound, which is determined by the methods 1a (CJC9) and 2 (CEC2). described in the Materials and Methods section below.

In accordance with another preferred embodiment, the invention relates to a specific stereoisomer of compounds of formula (I) with higher antiproliferative activity in tumor cell lines, such as SHA, compared to other stereoisomers of the corresponding compound, as determined by method 3 described in Materials and methods below.

In accordance with another preferred embodiment, the invention relates to a specific stereoisomer of compounds of formula (I) with improved solubility, for example, in water at pH 6.5, compared to other stereoisomers of the corresponding compound, as determined by method 4 described in the Materials and methods section below.

In accordance with another preferred embodiment, the invention relates to a specific stereoisomer of compounds of formula (I) with higher and improved effective magnetic permeability in Caco-2 (P _arr AB) in a monolayer culture of Caco-2, compared with other stereoisomers of the corresponding compounds, which is determined by method 5 described in the Materials and methods section below.

More specifically, the present invention encompasses compounds of general formula (I), which are disclosed in the Examples section below.

Particularly preferred are combinations of two or more of the above preferred embodiments of the invention.

In particular, preferred objects of the invention are compounds selected from the following compounds:

(gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -A- {4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

(+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -A- {4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

(-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -A- {4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

(gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -A- {6-methyl-4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

(gas) -5-bromo-A- [5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] -6methyl-4 - [(5-methylsulfonimidoyl) methyl] pyridin-2-amine ;

(gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -A- {6-methoxy-4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

(gas) -A- {6-chloro-4 - [(5-methylsulfonimidoyl) methyl] pyridin-2-yl} -5 fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine;

(gas) -2- {5- [(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl) amino} pyridin-4-yl) methyl] sulfonimidoyl} ethanol; (gas) -L / - (4 - {[5- (2-aminoethyl) sulfonimidoyl] methyl} pyridin-2-yl) 5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine;

{[(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methyl] (methyl) oxide-X ⁶ sulf anilidene} cyanamide;

(gas) ethyl {[(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methyl] (methyl) oxide-X ⁶ sulf anilidene } carbamate;

(gas) -1-ethyl-3 - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methyl] (methyl) oxide -X ⁶ sulfanilidene} urea;

(gas) -A- {[(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methyl] (methyl) oxide-X ⁶ sulf anilidene} acetamide;

5-fluoro-4- (4-fluoro-2-methoxyphenyl) -A- {4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine hydrochloride; enantiomer 2;

- 31 027226 (gas) -ethyl {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} -6-methoxypyridin-4-yl) methyl] (methyl) oxide-X ^b sulf anilidene} carbamate;

5-fluoro-4- (4-fluoro-2-methoxyphenyl) - (Y- {4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine hydrochloride; enantiomer 1;

(gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) - / Y- {6-fluoro-4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine; (gas) -2,2,2-trifluoro-LN [(2-fluoro-6- {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} pyridin-4yl) methyl] (methyl) oxide-X ⁶ -sulfan yl ideas} acetamide;

(+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) - (Y- {6-fluoro-4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

(-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) - (Y- {6-fluoro-4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

(gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) - (Y- {4 - [(5methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2yl} pyridin-2-amine;

(+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -U- {4 - [(5methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2yl} pyridin-2-amine;

(-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) - (Y- {4 - [(5methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2yl} pyridin-2-amine;

(+) - 2,2,2-trifluoro-U - [{[2- {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} -6- (trifluoromethyl) pyridine -4yl] methyl} (methyl) oxide-X ⁶ -sulfanyl ideas] acetamide;

(-) - 2,2,2-trifluoro-U - [{[2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} -6- (trifluoromethyl) pyridine -4yl] methyl} (methyl) oxide-X ⁶ -sulfanil ideas] acetamide; (gas) -4- (2-ethoxy-4-fluorophenyl) -5-fluoro- (Y- {6-fluoro-4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

- 32 027226 (gas) -M- {[(2 - {[4- (2-ethoxy-4-fluoro-phenyl) -5-fluoropyridin-2yl] amino} -6-fluoropyridin-4-yl) methyl] - (methyl) oxide-X ^b sulfanilidene} -2,2,2-trifluoroacetamide;

(+) - 4- (2-ethoxy-4-fluorophenyl) -5-fluoro-U- {6-fluoro-4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

(-) - 4- (2-ethoxy-4-fluorophenyl) -5-fluoro-U- {6-fluoro-4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

(gas) -A- {4 - [(5'-ethylsulfonimidoyl) methyl] pyridin-2-yl} -5-fluoro-4 (4-fluoro-2-methoxyphenyl) pyridin-2-amine;

(gds) -A- {6- (difluoromethyl) -4 - [(5methylsulfonimidoyl) methyl] pyridin-2-yl} -5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-amine;

(+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -U- {6-methyl-4 - [(5'methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine;

(-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -A- {6-methyl-4 - [(5'methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine, and also enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds.

The definitions of radicals given above for general considerations and when indicating preferred embodiments also apply to the final products of formula (I) and, accordingly, to the starting materials or intermediates that are required in each case to obtain the final product.

The present invention also relates to a method for producing compounds of formula (I) of the present invention, wherein котором-unprotected sulfoximines of formula (I), where K ⁵ is hydrogen, are reacted with appropriate agents to produce получением -functionalized sulfoximines of formula (I), where K ⁵ is as defined for the compound of formula (I) of the present invention, however, is not hydrogen.

in which the obtained compounds, if necessary, if necessary, are subjected to conversion using the appropriate (ΐ) solvents and / or (ΐΐ) bases or acids to obtain solvates, salts and / or solvates of salts of these compounds.

The present invention also relates to a method for producing compounds of formula (6), wherein K ¹ , K ² , K ³ and K ⁴ are as defined for a compound of formula (I) in accordance with the present invention, wherein the compounds of formula (5), where K ¹ , K ² , K ³ and K ⁴ have the meanings as defined for the compounds of formula (I) in accordance with the present invention

react with trifluoroacetamide and 1,3-dibromo-5,5-dimethylhydantoin in the presence of an alkali metal salt of tert-butanol in cyclic ether as a solvent to give a compound of formula (6)

- 33 027226

and in which the resulting compounds, if necessary, if necessary, are subjected to conversion using the appropriate (ΐ) solvents and / or (основ) bases or acids to obtain solvates, salts and / or solvates of salts of these compounds.

The present invention also relates to a method for producing compounds of formula (I), wherein the compounds of formula (6)

where K ¹ , K ² , K ³ and K ⁴ are as defined for the compound of formula (I) in accordance with the present invention, oxidized using an alkali metal salt of manganese acid in an aliphatic ketone of the formula C1-C ₂ -C (O) _-C1-C2 alkyl as solvent, followed by, if trifluoroacetyl group present in the compounds of formula (6) is not splintered during the above oxidation process, removing said trifluoroacetyl group by treatment of the resulting intermediate with an appropriate base in sleep Tov solvent to give compounds of formula (I), where R ⁵ is hydrogen

and in which the resulting compounds, if necessary, if necessary, are subjected to conversion using the appropriate (ΐ) solvents and / or (основ) bases or acids to obtain solvates, salts and / or solvates of salts of these compounds.

The present invention also relates to a method for producing compounds of formula (I), wherein the compounds of formula (6)

where K ¹ , K ² , K ³ and K ⁴ are as defined for the compound of formula (I) in accordance with the present invention, oxidized using an oxidizing agent based on peroxomonosulphate in a solvent selected from an aliphatic alcohol of the formula C ₁ -C ₃ - alkyl-OH, water and Ν, Ν dimethylformamide, or a mixture of these compounds, to obtain compounds of formula (I), where K ⁵ is hydrogen

and in which the resulting compounds, if necessary, as appropriate, are subjected

- 34,027,226 conversions using appropriate (ΐ) solvents and / or (ΐΐ) bases or acids to produce solvates, salts and / or solvates of salts of these compounds.

The present invention also relates to a method for producing compounds of formula (I), wherein the compounds of formula (5), wherein K ¹ , K ² , K ³ and K ⁴ are as defined for the compound of formula (I) in accordance with the present invention

react with trifluoroacetamide and 1,3-dibromo-5,5-dimethylhydantoin in the presence of an alkali metal salt of tert-butanol in cyclic ether as a solvent to give a compound of formula (6)

wherein said compounds of formula (6) are then oxidized using an appropriate oxidizing agent selected from an alkali metal salt of manganese acid and an oxidizing agent based on peroxomonosulfate in a solvent selected from an aliphatic ketone of the formula C ₁ -C ₂ -C (O) -C ₁ -C _2- alkyl, aliphatic alcohol of the formula C ₁ -C ₃ -alkyl-OH, water and Ν, Ν-dimethylformamide, or a mixture of these compounds, to obtain compounds of the formula (I), where K ⁵ is hydrogen

and in which the resulting compounds, if necessary, if necessary, are subjected to conversion using the appropriate (ΐ) solvents and / or (основ) bases or acids to obtain solvates, salts and / or solvates of salts of these compounds.

The present invention also relates to a method for producing compounds of formula (I), wherein the compounds of formula (14)

where K ¹ , K ³ and K ⁴ are as defined for the compound of formula (I) in accordance with the present invention, and where L0 is a leaving group, they react with a compound of formula (10)

Η ₂ Ν where K ² is as defined for the compound of formula (I) in accordance with the present invention, which is a palladium-catalyzed C-к cross-coupling reaction in the presence of chlorine (2-dicyclohexylphosphino-2 ', 4', 6 '-triisopropyl-1,1'-biphenyl) [2- (2-aminoethyl) phenyl] palladium (P) methyl tert-butyl ether adduct and 2- (dicyclohexylphosphino) -2', 4 ', 6'triisopropylbiphenyl as a catalyst and a ligand of palladium and potassium phosphate as a base in a mixture of toluene and Y-methylpyrrolidin-2-one as a solvent to give compound Inium of formula (I), where K ⁵ is hydrogen

- 35 027226

and in which the resulting compounds, if necessary, if necessary, are subjected to conversion using the appropriate (ΐ) solvents and / or (основ) bases or acids to obtain solvates, salts and / or solvates of salts of these compounds.

The present invention also relates to a method for producing compounds of formula (I), wherein the compounds of formula (16)

where K ¹ , K ³ and K ⁴ are as defined for the compound of formula (I) in accordance with the present invention, and where L0 is a leaving group, they react with a compound of formula (10)

where K ² is as defined for the compound of formula (I) in accordance with the present invention, which is a palladium-catalyzed C Ν cross-coupling reaction in the presence of chlorine (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl -1,1'-biphenyl) [2- (2-aminoethyl) phenyl] palladium (P) methyl tert-butyl ether adduct and 2- (dicyclohexylphosphino) -2 ', 4', 6'triisopropylbiphenyl as catalyst and palladium ligand and potassium phosphate as the base in a mixture of toluene and ^ methylpyrrolidin-2-one as solvent to give the compound th formula (I), where K ⁵ is C (O) OE1, followed by the reaction of these compounds of formula (I), where K ⁵ is C (O) OE1), with an alkali metal salt of an aliphatic alcohol of formula C ₁ -C ₄ alkyl-OH in the corresponding aliphatic alcohol to give compounds of formula (I), wherein K ⁵ is hydrogen

and in which the resulting compounds, if necessary, if necessary, are subjected to conversion using the appropriate (ΐ) solvents and / or (основ) bases or acids to obtain solvates, salts and / or solvates of salts of these compounds.

The present invention also relates to compounds of formula (5), wherein K ¹ , K ² , K ³ and K ⁴ are as defined for the compound of formula (I) in accordance with the present invention

as well as salts, solvates or salts of solvates of these compounds.

The present invention also relates to compounds of formula (6), wherein K ¹ , K ² , K ³ and K ⁴ are as defined for the compound of formula (I) in accordance with the present invention

- 36,027,226

as well as salts, solvates or salts of solvates of these compounds.

The present invention also relates to compounds of formula (14), wherein K ¹ , K ³ and K ⁴ are as defined for the compound of formula (I) in accordance with the present invention, and where L0 is a leaving group

as well as salts, solvates or salts of solvates of these compounds.

The present invention also relates to compounds of formula (16), wherein K ¹ , K ^3, and K ⁴ are as defined for compounds of formula (I) in accordance with the present invention, and where L0 is a leaving group

as well as salts, solvates or salts of solvates of these compounds.

The compounds of the present invention unexpectedly exhibit an extremely useful pharmacological and pharmacokinetic spectrum of action.

Thus, they can be used as drugs for the treatment and / or prevention of diseases of humans and animals.

As used herein, the term treatment includes prophylaxis.

The pharmaceutical activity of the compounds of the present invention may be explained by their activity as ECC9 inhibitors. Thus, the compounds of the general formula (I), as well as their enantiomers, diastereoisomers, salts, solvates and salts of solvates, are used as ECC9 inhibitors.

In addition, the compounds of the present invention exhibit an extremely high potency (as demonstrated by the low value! C ₅₀ in the analysis of SEC9 / CsT1) when inhibiting the activity of S1G9.

In the context of the present invention, the value! ₅₀ through C1G9 can be determined by the methods described in the Methods section below. Preferably, it is determined in accordance with method 1a (Analysis for C1G9 / CusT1 kinase) described in the Materials and Methods section below.

Surprisingly, it was found that compounds of the general formula (I), as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of these compounds selectively inhibit S1G9 in comparison with other cyclin-dependent protein kinases, preferably in comparison with S1G2. Thus, the compounds of general formula (I), as well as their pharmaceutically acceptable salts, are preferably used as selective C1G9 inhibitors.

The compounds of general formula (I) in accordance with the present invention exhibit a significantly higher degree of inhibition of S1G9 than S1G2.

In the context of the present invention, the value! C ₅₀ to S1G2 can be determined by the methods described in the Methods section below. Preferably, it is determined in accordance with method 2 (Analysis for C1G2 / CusH kinase) described in the Materials and Methods section below.

In addition, compared with C1G9 inhibitors. described in the prior art, the preferred compounds of the invention of general formula (I) exhibit surprisingly high force action in inhibiting the activity S1ZH9 at high concentrations of ATP, as demonstrated by the low value! C ₅₀ in the analysis of S1ZH9 / SusT1 kinase at high ATP concentrations. Thus, when using these compounds, there is a lesser probability that they will be displaced from the ATP-binding pocket of the C1G9 / CusT1 kinase due to the high intracellular concentration of ATP (K. Sore1apb e! A1., No. Tsige Keu1e \\ b Aegis Obsouegu 2006, 5, 730-739). In accordance with this property, the compounds of the present invention have, in particular, the ability to inhibit CEK9 / CusT1 in cells for a longer period of time compared to conventional kinase inhibitors that compete with ATP. This increases their effectiveness of the inhibitor against tumor cells with decreasing serum concentrations due to pharmacokinetic clearance after taking the dose of the drug by the patient or animal.

In the context of the present invention, the value Κ. ' ₅₀ according to SIC9 at high ATP concentrations can be determined by the methods described in the Methods section below. Preferably, it is determined in accordance with method 1b (Analysis by SIC9 / CusT1 kinase at high ATP concentrations) described in the Materials and Methods section below.

Also, the preferred compounds of the present invention according to formula (I) exhibit improved antiproliferative activity in tumor cell lines, for example, HeLa, as compared with the CIC9 inhibitors described in the prior art. In the context of the present invention, antiproliferative activity in tumor cell lines, for example, HeLa, is preferably determined in accordance with Method 3 (Proliferation Test) described in the Materials and Methods section below.

Also, the preferred compounds of the present invention according to the formula (I) unexpectedly exhibit improved solubility in water at pH 6.5 compared to the compounds described in the prior art.

In the context of the present invention, the solubility in water at pH 6.5 is preferably determined in accordance with method 4a (Equilibrium solubility analysis in a shake flask. Thermodynamic solubility in water) described in the Materials and methods section below.

Also, the preferred compounds of the present invention according to formula (I) are characterized by improved pharmacokinetic properties, for example, increased effective magnetic permeability in Caco-2 (P _arr A-B) in a monolayer culture of Caco-2 compared with the compounds described in the prior art .

Also, the preferred compounds of the present invention according to formula (I) are characterized by improved pharmacokinetic properties, for example, reduced efflux ratio (efflux ratio = P _arr B-A / P _arr A-B) from the basal to apical in the monolayer culture of Caco-2 according compared with the compounds described in the prior art.

In the context of the present invention, the effective magnetic permeability in Caco-2 from the basal to the apical (Papr AB) or efflux coefficient (which is defined as the ratio of ((Papr AB) / (P _apr AB)) is preferably determined according to with method 5 (Permeability Test in Saso-2) described in the Materials and Methods section below.

Also, preferred compounds of the present invention according to formula (I) do not show significant inhibition of carbonic anhydrase-1 or -2 (values Κ. _'50 of more than 10 mM) and therefore exhibit an improved side effect profile compared with SIC inhibitors described in the prior prior art containing sulfonamide group that inhibit carbonic anhydrase-1 or -2. In the context of the present invention, the inhibition of carbonic anhydrase-1 or -2 is preferably determined in accordance with method 6 (Test for the inhibition of carbonic anhydrase) described in the Materials and Methods section below.

Also an object of the present invention is the use of compounds of the general formula (I) of the present invention for the treatment and / or prevention of diseases, preferably diseases caused or associated with the activity of SIC9, in particular hyperproliferative diseases, viral infections and / or diseases of the cardiovascular system, more preferably hyperproliferative diseases.

The compounds of the present invention can be used to inhibit the activity or expression of SIC9. Therefore, it can be assumed that the compounds of formula (I) may be useful as therapeutic agents. Accordingly, in yet another embodiment of the invention, the present invention provides a method of treating diseases caused or associated with the activity of SIC9 by a patient in need of such treatment, which comprises applying an effective amount of a compound of the general formula (I) as defined above. In certain embodiments, diseases associated with CIC9 activity are hyperproliferative diseases, viral infections and / or diseases of the cardiovascular system, more preferably hyperproliferative diseases, in particular cancer.

The term “treatment” or “therapy” is used in the usual meaning of this document, that is, it means helping or caring for a person to alleviate, relieve symptoms, alleviate, improve a pathological condition, and combat a pathological condition caused by a disease or disorder, such as, for example, carcinoma .

The term patient includes organisms that may suffer from a disease associated with cell proliferation, or a disease associated with a decrease or insufficiency of programmed cell death (apoptosis), or which may be of any benefit by application

- 38,027,226 compounds of the present invention, such as, for example, humans or other animals. Preferably, the term human includes patients suffering from a disease associated with cell proliferation, or from a condition associated with such a disease, or who are susceptible to such a disease or condition, as described herein. The term other animals includes vertebrates, for example, mammals such as monkeys, sheep, cows, dogs, cats and rodents, such as mice, and other non-mammalian animals such as chickens, amphibians, reptiles, etc.

The term diseases caused or associated with the activity of SEC9 includes diseases that arise in connection with the activity of SEC9 or due to the activity of SEC9, for example, increased activity of SEA, as well as the pathological conditions associated with such diseases. Examples of diseases caused or associated with the activity of SEC9 include diseases resulting from an increased activity of SEC9 due to mutations in genes that regulate the activity of SEC9, such as LLCP7, NEXGM1 / 2 or 7cv-snRNA, or diseases resulting from increased activity of SEC9 due to due to activation of the SEC9 / cyclinT / RNA polymerase II complex by viral proteins, such as NGU-TLT or NTBU-TLC, or diseases resulting from increased activity of SEC9 due to activation of the mitogenic signaling pathway.

The term increased activity of SEC9 refers to an increased enzymatic activity of SEC9 compared to normal, healthy cells or to an increased activity of SEA, which leads to undesirable cell proliferation, reduced or insufficient apoptosis (programmed cell death), or mutations leading to constitutive activation of SEC9 .

The term hyperproliferative disease includes diseases in which unwanted or uncontrolled cell proliferation occurs, as well as diseases associated with a decrease or insufficiency of programmed cell death (apoptosis). The compounds of the present invention can be used for the prevention, suppression, blocking, reduction, reduction, control, etc. cell proliferation and / or cell division and / or to stimulate apoptosis. This method comprises administering to a patient in need of such treatment (including mammals, including humans) an amount of a compound of the present invention or a pharmaceutically applicable salt, hydrate or solvate of this compound, which is effective for treating or preventing this disease.

In the context of the present invention, hyperproliferative diseases include, but are not limited to, for example, psoriasis, keloids and other hyperplasias affecting the skin, endometriosis, bone diseases, proliferative angiogenic diseases or proliferative diseases of blood vessels, pulmonary hypertension, fibrotic diseases, proliferative diseases of mesangial cells, thick polyps colon, polycystic kidney disease, benign prostatic hyperplasia (BPH), and dense tumors such as breast, respiratory urine, brain, reproductive organs, digestive tract, urinary tract, eyes, liver, skin, head and neck, thyroid gland, parathyroid gland and their distant metastases. These diseases also include lymphomas, sarcomas and leukemias.

Examples of breast cancer include, but are not limited to, infiltrative ductal carcinoma, invasive lobular carcinoma, ductal carcinoma ίη δίΐιι and lobular carcinoma ίη δίΐιι, and breast carcinoma of dogs and cats.

Examples of cancer of the airways include, but are not limited to, small cell and non-small cell lung carcinomas, as well as bronchial adenoma and pleuro pulmonary blastoma and mesothelioma.

Examples of brain cancer include, but are not limited to, brain stem glioma and hypothalamic glioma, cerebellar astrocytoma, and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumors.

Tumors of male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal and vulvar cancer, and uterine sarcoma.

Digestive tract tumors include, but are not limited to, cancer of the anal canal, colon, colorectal cancer, cancer of the esophagus, gall bladder, stomach, cancer of the pancreas, cancer of the colon, cancer of the small intestine, cancer of the salivary gland, adenocarcinoma of the anal gland and mastocytoma.

Tumors of the urinary tract include, but are not limited to, cancer of the bladder, penis, kidney, renal pelvis, ureter, urethral cancer, and hereditary and sporadic papillary kidney cancer.

Eye cancer includes, but is not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma including the fibrolamellar variant and other variants), cholangiocarcinoma (cancer of the intrahepatic bile duct), and mixed hepatocellular cholangiocarcinoma.

Skin cancer includes, but is not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell cancer, non-melanocytic skin cancer, and mastocytoma.

- 39 027226

Head and neck cancer includes, but is not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, and lip and oral cancer, squamous cell carcinoma, and oral melanoma.

Lymphomas include, but are not limited to, AIDS-associated lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, Burkitt’s lymphoma, Hodgkin’s disease, and central nervous system lymphoma.

Sarcomas include, but are not limited to, soft tissue sarcoma, osteogenic sarcoma, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis, fibrosarcoma, hemangiosarcoma, hemangiopericytoma, and leiomyosarcoma.

Leukemias include, but are not limited to, acute myelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and nappy cell leukemia.

Fibrous proliferative diseases, i.e. pathological formation of the extracellular matrix, the treatment of which can be carried out using the compounds and methods of the present invention, include pulmonary fibrosis, atherosclerosis, restenosis, liver cirrhosis and proliferative diseases of mesangial cells, including kidney diseases such as glomerulonephritis, diabetic nephropathy, arteriolonecrotic nephrosclerosis, thrombotic syndromes microangiopathies, transplant rejection and glomerulopathy.

Other pathological conditions in humans or other mammals that can be treated by administering the compounds of the present invention include tumor growth, retinopathy, including diabetic retinopathy, retinal vein ischemic occlusion, Terry syndrome and age-related macular degeneration, rheumatoid arthritis, psoriasis, and bullous diseases, associated with the formation of subepidermal vesicles, including bullous pemphigoid, polymorphic erythema and herpetiform dermatitis.

The compounds of the present invention can also be used for the prevention and treatment of diseases of the respiratory tract and lungs, diseases of the gastrointestinal tract, as well as diseases of the bladder and biliary tract.

The diseases indicated above are typical of humans, however, they also exist with a similar etiology in other animals, including mammals, and the treatment of these diseases can be carried out by administering the compounds of the present invention.

In accordance with another aspect of the present invention, the compounds of the present invention are used in a method for the treatment and / or prevention of infectious diseases, in particular viral infections. The cause of viral infections, including opportunistic diseases, is retroviruses, hepatadaviruses, herpes viruses, flaviviruses and / or adenoviruses. According to another preferred embodiment of this method, retroviruses are selected from lentiviruses or oncoretroviruses, the lentivirus selected from the group consisting of NSU-1, SHU-2, PU, NU, PU, 8SU, SAEU, UMU or E! AU, preferably SHU-1 or SHU-2, and the oncoretrovirus is selected from the group: NTL, NTL-P or VIU. In accordance with another preferred embodiment of this method, the hepatadavirus is selected from HLD, C8HU or \ UNU, preferably HLW, herpes virus is selected from the group comprising H8U I, H8U II, EVU, U2U, NSMU or NNU 8, preferably NSMU, and flaviviruses selected from NSO, West Nile virus or yellow fever virus.

The compounds of general formula (I) can also be used for the prevention and / or treatment of diseases of the cardiovascular system, such as cardiac hypertrophy, congenital heart disease in adults, aneurysm, stable angina pectoris, unstable angina pectoris, angina pectoris, angioedema, aortic valve stenosis, aortic aneurysm, arrhythmia, arrhythmogenic dysplasia of the right ventricle, arteriosclerosis, arteriovenous malformation, atrial fibrillation, Behcet syndrome, bradycardia, cardiac tamponade, cardiomegaly, congestive cardi omiopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, prevention of cardiovascular diseases, carotid stenosis, intracerebral hemorrhage, Cherge-Strauss syndrome, diabetes, Ebstein's anomaly, Eisenmenger complex, cholesterol embolism, heart disease, bacterial endocarditis, heart disease heart failure, heart valve disease, acute cardiovascular disease, epidural hematoma, subdural hematoma, Hippe disease i-Lindau, hyperemia, hypertension, pulmonary hypertension, hypertrophy, left ventricular hypertrophy, right ventricular hypertrophy, hypoplasia of the left half of the heart, hypotension, Charcot’s syndrome, coronary heart disease, Klippel-Trenone Weber syndrome, Wallenberg syndrome, PT interval elongation syndrome mitral valve prolapse, Moyamoy disease, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral blood vessel diseases, phlebitis, nodose polyarth rheitis, pulmonary atresia, Raynaud's disease, restenosis, Sneddon syndrome, stenosis, superior vena cava syndrome, X syndrome, tachycardia, Takayasu syndrome, hereditary hemorrhagic telangiectasia, telangiectasia, temporal arteritis, tetralogy of Fallot, thrombosis, thrombosis, thrombosis, thrombosis valves, varicose veins, vascular diseases, vasculitis, vasospasm, ventricular fibrillation, Williams syndrome, peripheral vascular disease, varicose veins and

- 40 027226 foot ulcer, deep vein thrombosis, Wolf-Parkinson-White syndrome.

Preferably, these compounds are used for the prevention and / or treatment of heart hypertrophy, congenital heart disease in adults, aneurysms, angina pectoris, angina pectoris, arrhythmias, prevention of diseases of the cardiovascular system, cardiomyopathy, congestive heart failure, myocardial infarction, pulmonary hypertension, hypertrophy restenosis, stenosis, thrombosis and arteriosclerosis.

Also an object of the present invention is the use of compounds of the general formula (I) of the present invention for the treatment and / or prophylaxis of diseases, in particular, the above diseases.

Also an object of the present invention is the use of compounds of the general formula (I) of the present invention for the treatment and / or prevention of diseases, in particular lung carcinoma, in particular non-small cell lung carcinoma, prostate carcinoma, in particular hormone-independent human prostate carcinoma, carcinomas of the cervix uteri, including multiresistant carcinoma of the human cervix, colorectal carcinomas, melanomas, carcinomas of the ovary or leukemia, in particular acute myelocytic leukemia.

Also, an object of the present invention are compounds of the present invention, which can be used in a method for the treatment and / or prevention of the above diseases.

A preferred object of the present invention are the compounds of the present invention used for the treatment and / or prophylaxis of lung carcinoma, in particular non-small cell lung carcinoma, prostate carcinoma, in particular hormone-independent human prostate carcinoma, cervical carcinoma, including multiresistant human cervical carcinoma colorectal carcinomas, melanomas, carcinomas of the ovary or leukemia, in particular acute myelocytic leukemia.

Also an object of the present invention is the use of the compounds of the present invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the above diseases.

A preferred object of the present invention is the use of the compounds of the present invention for the manufacture of a medicament for the treatment and / or prevention of lung carcinoma, in particular non-small cell lung carcinoma, prostate carcinoma, in particular hormone-independent human prostate carcinoma, cervical carcinoma, including multidrug carcinoma human cervix, colorectal carcinomas, melanomas, ovarian carcinomas or leukemia, in particular acute myelocytic th leukemia.

Also, an object of the present invention is a method for the treatment and / or prevention of diseases, in particular the above diseases, using an effective amount of the compounds of the present invention.

A preferred object of the present invention is a method for the treatment and / or prevention of lung carcinoma, in particular non-small cell lung carcinoma, prostate carcinoma, in particular hormone-independent human prostate carcinoma, cervical carcinoma, including multiresistant human cervical carcinoma, colorectal carcinoma, melanoma, ovarian carcinoma or leukemia, in particular acute myelocytic leukemia.

Another aspect of the present invention relates to pharmaceutical combinations comprising a compound of general formula (I) of the present invention in combination with at least one or more additional active ingredients.

As used herein, the term pharmaceutical combination refers to a combination of at least one compound of general formula (I) of the present invention as an active ingredient with at least one other active ingredient and with other additional ingredients, carriers, diluents and / or solvents or without them.

Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of general formula (I) of the present invention in combination with an inert, non-toxic, pharmaceutically acceptable excipient.

As used herein, the term pharmaceutical composition refers to a galenic preparation of at least one pharmaceutically active substance with at least one additional ingredient, carrier, diluent and / or solvent.

Another aspect of the present invention relates to the use of pharmaceutical combinations and / or pharmaceutical compositions of the present invention for the treatment and / or prophylaxis of diseases, in particular the above diseases.

The compounds of formula (I) can be used as a separate pharmaceutical preparation or in combination with one or more additional drugs, provided that the combination of these substances does not lead to the appearance of negative effects that make the use of such a combination impossible. Such a pharmaceutical combination includes the use of a unit dosage form that contains a compound of formula (I) and one or more additional drugs, as well as the use of a compound of formula (I) and each additional drug in separate dosage forms . For example, a patient may take a compound of formula (I) and a drug at the same time as a single oral dosage composition, such as a tablet or capsule, or each substance may be taken in separate dosage forms.

When using separate dosage forms, the compound of the formula I, as well as one or more additional drugs, can be used practically at the same time (for example, in parallel) or separately at different times (for example, sequentially).

In particular, the compounds of the present invention can be used in the form of a fixed-dose combination preparation or separately with other antitumor agents, such as alkylating agents, antimetabolites, antitumor agents derived from plants, hormone therapy agents, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors targeted drugs, antibodies, interferons and / or biological response modifiers, antiangiogenic drugs and other antitumor drugs tween funds. In this regard, the following is a non-restrictive list of examples of secondary agents that can be used in combination with the compounds of the present invention:

alkylating agents include, but are not limited to, и-oxide of mustard mustard, cyclophosphamide, ifosfamide, thiotepa, ranimustine, nimustine, temozolomide, altretamine, apaziquon, brostallicin, bendamustine, carmustine, estramustine, fotemustine, moltofolmoltofolmfolf golofoz; alkylating compounds, platinum complex compounds include, but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin and satraplatin;

antimetabolites include, but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (alone or in combination with leucovorin), tegafur, doxifluridine, karmofur, cytarabine, cytarabine oxphosphate, enocytabin tin, heptocytabincidazin, heptocytabincidabine, heptocytabinde, gemcitabincidin , cladribine, klofarabin, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan, nonlarabin, nolatrexed, oxphosphite, premetrexed disodium, pentostatin, pelitrexol, raltitrexed, triapin, tinrexin vinrethrex;

hormone therapy agents include, but are not limited to, exemestane, Lupron, anastrozole, doxercalciferol, fadrozole, formestane, type 1 11-beta hydroxysteroid dehydrogenase inhibitors, 17-alpha hydroxylase / 17,20 lyase inhibitors, such as abiraterone acetate, 5-alpha reductase inhibitors such as finasteride and episteride, antiestrogens such as tamoxifen citrate and fulvestrant, Trelstar, toremifene, raloxifene, lazoxifen, letrozole, antiandrogens such as bicalutamide, flutamide, mifepristone, nilutamide, casodex and antiprogest the specified substances;

antitumor agents obtained from plants include, for example, agents selected from mitosis inhibitors, for example epothilones, such as sagopilon, ixabepilone and epothilone B, vinblastine, vinflunine, docetaxel and paclitaxel;

Cytotoxic topoisomerase inhibitors include, among others, aclarubicin, doxorubicin, amonafid, belotekan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotekan, irinotecan, topotecan, edotecarin, epimbitsin, etoposide, eksatekan, gimatekan, lurtotekan, mitoxantrone, pirambitsin, piksantron, rubitecan, sobuzoxan, tafluposide and combinations of these substances;

immunological agents include interferons, such as interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamama-1a and interferon gamama-p1, and other immunity enhancers, such as b19- [b2 and other derivatives of GO2 , filgrastim, lentinan, sisofilan, TeraCis, ubenimex, aldesleukin, alemtuzumab, VAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab, ozogamicin, ibritumumab, imichimod, lengograstim, santigramimantha, lentramanimantha, melanthymantha, lentramanimantha, m , tazonermin, tkley in, timalazin, tositumomab, Vimlizin, epratuzumab, mitumomab, oregovomab, pemtumomab Provenge and / Rtouepde; melanoma vaccine (production of Mepa1);

biological response modifiers are means that modify the mechanisms of protection of living organisms or biological reactions, such as the viability, development or differentiation of tissue cells, so as to give them anti-tumor activity; such agents include, for example, christening, lentinan, sisofiran, pitsibanil, RgoMipe and ubenimex;

anti-angiogenic agents include, without limitation, acitretin, aflibercept, angiostatin, aplidine, azentar, aksitinib, retsentin, bevacizumab brivanib alaninate, tsilengtid, combretastatin, ΌΆ8Τ, endostatin, fenretinide, halofuginone, pazopanib, ranibizumab, rebimastat, removab, Revlimid, sorafenib, vatalanib, squalamine, sunitinib, telatinib, thalidomide, Ukraine and vitaxin;

antibodies include, but are not limited to, trastuzumab, cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept, oregovomab and alemtuzumab;

DRUG inhibitors, such as sorafenib, ΌΆ8Τ, bevacizumab, sunitinib, retsentin, axitinib, aflibercept, telatinib, brivanib alaninate, vatalanib, pazopanib and ranibizumab; palladium preparations EORC inhibitors (HEK1) such as cetuximab, panitumumab, vectibix, gefitinib, erlotinib and Zaktima;

- 42 027226 HEK2 inhibitors such as, for example, lapatinib, tratuzumab and pertuzumab;

tTOK inhibitors such as, for example, temsirolimus, sirolimus / rapamycin, and everolimus;

c-Me inhibitors !;

ROCK and ACT inhibitors;

RNS inhibitors such as roskovitin and flavopyridol;

fission spindle assembly control point inhibitors and targeted anti-mitotic agents such as PKB inhibitors, Aigog kinase inhibitors (eg Hesperadine), checkpoint kinase inhibitors and K8P inhibitors;

NEAS inhibitors such as, for example, panobinostat, vorinostat, M8275, proteinostat and LBH589; H8P90 and H8P70 inhibitors;

proteasome inhibitors such as bortezomibi carfilzomib;

serine / threonine kinase inhibitors, including MEK inhibitors (such as, for example, COEA 119) and CaH inhibitors, such as sorafenib;

farnesyl transferase inhibitors such as, for example, tipifarnib;

tyrosine kinase inhibitors, including, for example, dasatinib, nilotibib, EA5T, bosutinib, sorafenib, bevacizumab, sunitinib, ΑΖΌ2171, axitinib, aflibercept, telatinib, imatinib mesylate, brivanib alaninib, pazibitibum, pazibitum , lapatinib, tratuzumab, pertuzumab and c-KH inhibitors; palladium preparations, masitinib;

vitamin торов receptor agonists;

BC1-2 protein inhibitors such as obatoclax, oblimersen sodium and gossypol; differentiation cluster receptor antagonists 20 such as, for example, rituximab; ribonucleotide reductase inhibitors such as, for example, gemcitabine;

agonists of receptor 1 ligand inducing apoptosis and associated with tumor necrosis factor such as, for example, mapatumumab;

5-hydroxytryptamine receptor antagonists such as, for example, TEU598, xaliprod, palonosetron hydrochloride, granisetron, Tsindol and AB-1001;

integrin inhibitors, including alpha5-beta1 integrin inhibitors such as, for example, E7820, 1§M 6425, volociximab and endostatin;

androgen receptor antagonists, including, for example, nandrolone decanoate, fluoxymesterone, Android, ProstAid, andromustine, bicalutamide, flutamide, apo-cyproterone, apo-flutamide, chlormadinone acetate, Androcur, Tabi, cyproterone acetate and nilutamide;

aromatase inhibitors, such as, for example, anastrozole, letrozole, testolactone, exemestane, aminoglutetimide and formestane;

matrix metalloproteinase inhibitors;

other anticancer agents, including, for example, alitretinoin, ampligen, atrasentan bexarotene, bortezomib, bosentan, calcitriol, exisulind, fotemustine, ibandronic acid, miltefosine, mitoxatron, Casparaginase, procarbazine, dacarbazine, hydroxycarbazarbazotene, hydroxycarbaztene, nitrocarbazene , canfosamide, darinaparsin and tretinoin.

The compounds of the present invention can also be used to treat cancer in combination with radiotherapy and / or surgery.

Typically, the use of cytotoxic and / or cytostatic agents in combination with a compound or composition of the present invention:

(1) it will provide higher efficacy in reducing tumor growth or even destruction of the tumor compared to taking each substance separately, (2) it will allow taking smaller amounts of chemotherapeutic agents, (3) it will allow prescribing chemotherapeutic treatment that is well tolerated by the patient and has fewer harmful drugs the complications observed with chemotherapy with one substance and with some other combination therapies (4) will allow treating a wider range of different types of cancer in a mammal x, especially in humans, (5) increase the percentage of positive clinical response among treated patients, (6) increase the survival time among treated patients compared to standard chemotherapy, (7) prolong tumor development time and / or (8) ensure effectiveness and tolerance, at least at the same level as substances used separately, in comparison with known cases where other combinations of anti-cancer agents cause an antagonistic effect.

In addition, the compounds of formula (I) can be used (on their own or in pharmaceutical compositions) for diagnosis or in research or as analytical standard samples and for other similar purposes known to those skilled in the art.

The compounds of the present invention may have systemic and / or topical effects. For these purposes, they can be applied using appropriate methods of drug administration, for example, orally, parenterally, pulmonally (inhalation), nasal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival, through the ears or using implants or stents.

The compounds of the present invention can be used in such forms for use that are consistent with these methods of drug administration.

Suitable forms for oral administration are those which function in accordance with the prior art and which, when used, release the compounds of the present invention quickly and / or according to modified kinetics, and which contain the compounds of the present invention in crystalline and / or non-crystalline form and / or in a dissolved form, such as, for example, tablets (with or without coating, for example, with an enteric coating or with a coating which is practically insoluble, or cat swarm dissolves with a delay and controls the release of the compound of the present invention), oral tablets or film-coated capsules, film-coated lyophilisates, capsules (e.g. hard or soft gelatin capsules), sugar-coated tablets, granules microspheres, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration may be carried out without an absorption step (e.g., intravenous administration, intraarterial administration, intracardial administration, intraspinal administration or endolumbar administration) or may include absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Examples of forms suitable for other routes of administration are pharmaceutical forms for inhalation (inter alia, powder inhalers, aerosol inhalers), nasal drops, solutions or sprays, tablets for lingual, sublingual or buccal administration, capsules, capsules, implants, capsules, coated film coating, suppositories, preparations for administration through the eyes or ears, vaginal capsules, aqueous suspensions (lotions, mixtures for shaking), lipophilic suspensions, ointments, creams, transdermal therapeutic systems topics (e.g. patches), lotion, pastes, foams, dusty powders, implants or stents.

The compounds of the present invention can be converted to the listed forms for use. This can occur in a manner known per se by mixing with inert, non-toxic, pharmaceutically acceptable excipients. These excipients include, but are not limited to, carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g. sodium dodecyl sulfate, polyoxy sorbitan oleate), binders (e.g. polyvinyl pyrrolidone ), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, such as, for example, ascorbic acid), dyes, e.g., inorganic pigments, such as, for example ep, iron oxides) and substances Correcting taste and / or odor.

The present invention also provides drugs containing at least one compound of the present invention, usually together with one or more inert, non-toxic pharmaceutically acceptable excipients, as well as their use for the above purposes.

When the compounds of the present invention are used as medicines for humans or animals, they can be administered in pure form or in the form of a pharmaceutical composition containing, for example, 0.1-99.5% (more preferably 0.5-90 %) of the active ingredient in combination with one or more inert, non-toxic pharmaceutically acceptable excipients.

Regardless of the route of administration chosen, the compounds of the present invention of general formula (I) and / or the pharmaceutical compositions of the present invention are produced in pharmaceutically acceptable dosage forms using standard methods known to those skilled in the art.

Actual dosages and modes of administration of the active ingredients in the pharmaceutical compositions of the present invention may vary to obtain an amount of the active ingredient that is effective to produce a desired response to therapy for a particular patient that is not toxic to the patient.

Materials and methods

In the tests and examples below, unless otherwise indicated, percentages are given by weight ratio; fractions are also given by weight. Solvent ratios, dilution rates, and concentrations indicated for liquid / liquid solutions are in each case based on a volume ratio.

Testing by examples was carried out using certain types of biological analysis one or more times. When testing more than once, the data are either average values or median values, while the average value, which is also called the arithmetic mean, is the sum of the obtained values divided by the number of tests performed, and the median value is the median value from the group of values, when they are arranged in order from lowest to highest or vice versa. If the number of values in the data set is odd, the median value is the median value. If the number of values in the data set is even, the median value is the arithmetic average of two median values.

Selected biological studies of the examples were performed one or more times. If the selected biological studies of the examples were performed several times, the biological analysis data are the average values or median values calculated using the data sets obtained when testing one or more synthesized samples.

The pharmacological properties of ίη νίίΓΟ compounds can be determined in accordance with the following methods and analysis methods.

la. Analysis by SIC9 / CusT1 kinase.

The inhibitory activity against SIC9 / SucT1 compounds of the present invention was determined using analysis of SIC9 / SucT1 by TK-RACET in accordance with the description in the paragraphs below.

Recombinant human H18-labeled CIC9 and CucT1 full length expressed in insect cells and purified using S-affinity chromatography were purchased from ytodep (CaB Νο RU4131). As a substrate for the kinase reaction, we used the biotinylated peptide Biotin-P ^ -Y ^ RBKBRUKLBEO (C-terminus in the amide form), which can be purchased, for example, from the company TEKGSH Rörbbe Tesbpo1od1e8 (Berlin, Germany).

For analysis, 50 nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a small 384 black microtiter microtiter plate (Otetshet Βίο-Ope, Frickenhausen, Germany), 2 μl of SIC9 / CusT1 solution in an aqueous test buffer was added [50 mmol of Tp8 / HC1 pH 8.0, 10 mmol of MdC1 ₂ , 1.0 mmol of dithiothreitol, 0.1 mmol of sodium orthovanadate, 0.01% (volumetric content) Vop1be1-P40 (§1§ta)], and the mixture was incubated in for 15 min at a temperature of 22 ° C in order to provide preliminary binding of test compounds first with the enzyme before the start of the kinase reaction. Then, the kinase reaction was started by adding 3 μl of adenosine triphosphate solution (ATP, 16.7 μmol, final concentration in 5 μl of the analyzed volume - 10 μmol) and substrate (1.67 μmol final concentration in 5 μl of the analyzed volume - 1 μmol) in the test buffer; the resulting mixture was incubated during the reaction time, 25 min, at a temperature of 22 ° C. The concentration of CIC9 / CusT1 was regulated in accordance with the activity of the enzyme in order to maintain the analysis in a linear range, the usual concentration of enzymes was in the range of 1 μg / ml. The reaction was stopped by adding 5 μl of a solution of reagents for TKRCET detection (0.2 μmol streptavidin-XB665 [C18Bu Vyu88au8, Codole, France] and 1 nmol antiKV (pget807 / pgeg811) -antibody, production of VI Pbtstep [# 558389 ] and 1.2 nmol BACSE EI- ^ 1024 labeled anti-mouse βθ antibodies [Regksh-E1teg, product No. AI0077]) in an aqueous EITA solution (100 mmol EITA, 0.2% (w / v) bovine serum albumin in 100 mmol HEPEG / IAOH pH 7.0).

The resulting mixture was incubated for 1 h at a temperature of 22 ° C in order to ensure the formation of a complex between the phosphorylated biotinylated peptide and the developing reagent. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonant energy transfer from europium-labeled chelate to streptavidin-Xb. Correspondingly, fluorescence emission at a wavelength of 620 and 665 nm after excitation at 350 nm was measured using an NTSC reader, for example, PuBe81ag (WMO BaBeCnO1O81e8. Offenburg, Germany) or U1e \ u1u \ (RegktE1teg). An emissivity at 665 and 622 nm was taken as a measure of the amount of phosphorylated substrate.

Data normalized (enzyme reaction without inhibitor = 0% inhibition, all other test components + no enzyme = 100% inhibition). Test compounds were usually tested on the same microtiter plate at 11 different concentrations in the range of 20 μmol-0.1 nmol (20, 5.9, 1.7, 0.51, 0.15 μmol, 44 nmol, 13, 3.8 , 1.1, 0.33 and 0.1 nmol, dilution series were prepared separately before analysis at a 100-fold dilution of the mother liquor in DMSO by serial dilutions of 1: 3.4) in duplicate values for each concentration, and then the calculation was performed quantities Κ. ' ₅₀ four-parameter logistic equation using in-house software.

lb. Analysis by SIC9 / CusT1 kinase at high ATP concentrations.

The inhibitory activity against SIC9 / SucT1 compounds of the present invention at high ATP concentrations after pre-incubation of the enzyme and test compounds was determined using SIC9 / SucT1 analysis by TK-RACET as described in paragraphs

- 45,027,226 below.

Recombinant human Ηίδ-labeled SEC9 and CusT1 full length expressed in insect cells and purified using affinity chromatography at No.-GA were purchased from Shuigodep (Ca !. Νο РУ4131). As a substrate for the kinase reaction, the biotinylated peptide Biotin-TShK-U ^ Pb ^ RUKKEO (C-terminus in amide form) was used, which can be purchased, for example, from the TEKEM Reryye Tesbio1od1e5 company (Berlin, Germany).

For analysis, 50 nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a small 384 black microtiter microtiter plate (Ogeszeg Oö-Oie, Frickenhausen, Germany), 2 μl of SEC9 / CusT1 solution in an aqueous test buffer was added [50 mmol Tg / HO pH 8.0, 10 mmol MdCl ₂ , 1.0 mmol dithiothreitol, 0.1 mmol sodium orthovanadate, 0.01% (volumetric content) No.-! P40 (81 dt)], and the mixture was incubated for 15 min at a temperature of 22 ° C in order to provide preliminary binding of test compounds with the enzyme before starting the kinase reaction. Then, a kinase reaction was started by adding 3 μl of adenosine triphosphate solution (ATP, 3.3 mmol, final concentration in 5 μl of the analyzed volume - 2 mmol) and substrate (1.67 μmol final concentration in 5 μl of the analyzed volume - 1 mmol) in the test buffer; the resulting mixture was incubated during the reaction time, 25 min, at a temperature of 22 ° C. The concentration of CEC9 / CusT1 was regulated in accordance with the activity of the enzyme in order to maintain the analysis in a linear range, the usual concentration of enzymes was in the range of 0.5 μg / ml. The reaction was stopped by adding 5 μl of a solution of reagents for TK-RKET detection (0.2 μmol streptavidin-XB665 | St5Yo Vyuccauk, Codole, France] and 1 nmol of anti-KB (p8eg807 / p8eg811) -antibody, production of VO Ragtsstep [# 558389 ] and 1.2 nmol EACSE EI \ U1024 labeled anti-mouse antibodies to mouse [Regksh-E1teg, product No. AE0077]) in an aqueous solution of EOTA (100 mmol EETA, 0.2% (w / v) bovine serum albumin in 100 mmol HEPE8 / NUN pH 7.0).

The resulting mixture was incubated for 1 h at a temperature of 22 ° C in order to ensure the formation of a complex between the phosphorylated biotinylated peptide and the developing reagent. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonant energy transfer from europium-labeled chelate to streptavidin-Xb. Correspondingly, fluorescence emission at a wavelength of 620 nm and 665 nm after excitation at 350 nm was measured using a reader for NTSC, for example, CuBu! Ag (WMO baB! Esbio1od1e5, Offenburg, Germany) or U1e \\! And \ (RegkshE1teg) . An emissivity of 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate. Data normalized (enzyme reaction without inhibitor = 0% inhibition, all other test components + no enzyme = 100% inhibition). Test compounds were usually tested on the same microtiter plate at 11 different concentrations in the range of 20 μmol-0.1 nmol (20, 5.9, 1.7, 0.51, 0.15 μmol, 44 nmol, 13, 3.8 , 1.1, 0.33 and 0.1 nmol, dilution series were prepared separately before analysis at a 100-fold dilution of the mother liquor in DMSO by serial dilutions of 1: 3.4) in duplicate values for each concentration, and then the calculation was performed spacecraft values using the four-parameter logistic equation using the internal laboratory software of security.

2a. Analysis by SEC2 / Sous kinase.

The inhibitory activity in relation to CEC2 / CECE of the compounds of the present invention was determined using analysis CEC2 / CECE by TK-RET as described in the paragraphs below:

Recombinant fusion proteins of human O8T and SEK2 human and O8T and human СеЕ, expressed in insect cells (8T9) and purified using affinity chromatography on glutathione sepharose, were purchased from Progoit OTN (Freiburg, Germany). As a substrate for the kinase reaction, the biotinylated peptide Biotin-TMK-UKR ^ RUZZHO (C-terminus in amide form), which can be purchased, for example, from EEKGM Rerye Tesypo1od1e8 (Berlin, Germany), was used.

For analysis, 50 nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a small 384 black microtiter microtiter plate (Ogeszeg Vu-Ope, Frickenhausen, Germany), 2 μl of the SEC2 / СеЕ solution in an aqueous test buffer was added [50 mmol of TG18 / HC1 pH 8.0, 10 mmol of MDCl ₂ , 1.0 mmol of dithiothreitol, 0.1 mmol of sodium orthovanadate, 0.01% (volume content) No. WB-P40 (81 dt)], and the mixture was incubated for 15 min at a temperature of 22 ° C in order to provide preliminary binding of test compounds enzyme before kinase reaction. Then, a kinase reaction was started by adding 3 μl of adenosine triphosphate solution (ATP, 16.7 μmol, final concentration in 5 μl of the analyzed volume - 10 μmol) and substrate (1.25 μmol final concentration in 5 μl of the analyzed volume - 0.75 μmol) in the test buffer; the resulting mixture was incubated during the reaction time, 25 min, at a temperature of 22 ° C. The concentration of CEC2 / CCE was regulated in accordance with the activity of the enzyme in order to maintain the analysis in a linear range; the usual concentration of enzymes was in the range of 130 ng / ml. The reaction was stopped by adding 5 μl of a solution of reagents for TK-RKET detection (0.2 μmol streptavidin-XB665 [C1Byu Vyuccauk, Codole, France] and 1 nmol of anti-KB (p8eg807 / p8eg811) -antibody, production of Pbactsdep [# 558389 and 1 2 nmol ΕΑΝίΈ EI-U1024 labeled antibody to mouse [Regksh-E1teg, product No. .0077]) in an aqueous solution of ΕΌΤΆ (100 mmol ΕΌΤΑ, 0.2% (w / v) bovine serum albumin in 100 mmol HEPE8 / No. OH pH 7.0).

The resulting mixture was incubated for 1 h at a temperature of 22 ° C in order to ensure the formation of a complex between the phosphorylated biotinylated peptide and the developing reagent. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonant energy transfer from europium-labeled chelate to streptavidin-Xb. Correspondingly, fluorescence emission at a wavelength of 620 nm and 665 nm after excitation at 350 nm was measured using a reader for TK-RKET, for example, PuLuyag (WMO LaBeCbO1o1e8, Offenburg, Germany) or U1e \ u1u \ (Regksh-E1teg). An emissivity of 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate. Data normalized (enzyme reaction without inhibitor = 0% inhibition, all other test components + no enzyme = 100% inhibition). Test compounds were usually tested on the same microtiter plate at 11 different concentrations in the range of 20 μmol - 0.1 nmol (20, 5.9, 1.7, 0.51, 0.15 μmol, 44 nmol, 13, 3.8 , 1.1, 0.33 and 0.1 nmol, dilution series were prepared separately before analysis at a 100-fold dilution of the mother liquor in DMSO by serial dilutions of 1: 3.4) in duplicate values for each concentration, and then the calculation was performed quantities Κ. ' ₅₀ four-parameter logistic equation using in-house software.

2b. Analysis by SEC2 / CusE kinase at high ATP concentrations.

The inhibitory activity with respect to CE1 <2 / ССЕ of the compounds of the present invention at 2 mmol of adenosine triphosphate (ATP) was determined using the analysis of СЭК9 / СусТ1 by TK-RKET (TK-RKET = T1te Ke5о1еД Р1иогеsesepsse Епегду ТпапкРерес-resistant energy) as described in the paragraphs below.

Recombinant fusion proteins of human O8T and SEK2 human and O8T and human ССЕ expressed in insect cells (819) and purified using affinity chromatography on glutathione sepharose were purchased from RgoOite OTN (Freiburg, Germany). As a substrate for the kinase reaction, the biotinylated peptide Biotin-Tyk-UKRKBRUKEBEO (C-terminus in amide form), which can be purchased, for example, from the company DECEM Rerye Tespo1od1e8 (Berlin, Germany), was used.

For analysis, 50 nl of a 100-fold concentrated solution of the test compound in DMSO was pipetted into a small 384 black microtiter microtiter plate (Ogeszeg Vu-Ope, Frickenhausen, Germany), 2 μl of the SEC2 / СеЕ solution in an aqueous test buffer was added [50 mmol TpUNS1 pH 8.0, 10 mmol MdC1 ₂ , 1.0 mmol dithiothreitol, 0.1 mmol sodium orthovanadate, 0.01% (volume content) No. Ш0е1-P40 (81 dt)], and the mixture was incubated for 15 min at at a temperature of 22 ° C in order to provide preliminary binding of test compounds to an enzyme before starting a kinase reaction. Then, the kinase reaction was started by adding 3 μl of ATP solution (3.33 μmol final concentration in 5 μl of the analyzed volume - 2 μmol) and substrate (1.25 μmol final concentration in 5 μl of the analyzed volume - 0.75 μmol) in the test buffer; the resulting mixture was incubated during the reaction time, 25 min, at a temperature of 22 ° C. The concentration of CEC2 / CCE was regulated in accordance with the activity of the enzyme in order to maintain the analysis in a linear range, the usual concentration of enzymes was in the range of 15 ng / ml. The reaction was stopped by adding 5 μl of a solution of reagents for TK-RKET detection (0.2 μmol streptavidin-XB665 [C18Byu B1o88au8, Codole, France] and 1 nmol of anti-KB (p8eg807 / p8eg811) antibody, production of VO Pbtstep [# 558389 ] and 1.2 nmol ί-ΑΝίΈ EI-U1024 of labeled anti-mouse antibodies! §O mouse [Regksh-E1teg, product no. ΑΌ0077, alternatively cryptate-labeled terbium antibody anti-mouse O ^, production of C18Nyu Vyu88au8] can be used in aqueous EETA solution (100 mmol EOTA, 0.2% (w / v) bovine serum albumin in 100 mmol HEPE8 / NO OH pH 7.0).

The resulting mixture was incubated for 1 h at a temperature of 22 ° C in order to ensure the formation of a complex between the phosphorylated biotinylated peptide and the developing reagent. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonant energy transfer from europium-labeled chelate to streptavidin-Xb. Correspondingly, fluorescence emission at a wavelength of 620 nm and 665 nm after excitation at 350 nm was measured using a reader for TK-RKET, for example, PuBuyag (WMO LaBeCbO1o1e8, Offenburg, Germany) or U1e \ u1u \ (Regksh-E1teg). An emissivity of 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate. Data normalized (enzyme reaction without inhibitor = 0% inhibition, all other test components + no enzyme = 100% inhibition). Test compounds were usually tested on the same microtiter plate at 11 different concentrations in the range of 20 μmol-0.1 nmol (20, 5.9, 1.7, 0.51, 0.15 μmol, 44 nmol, 13, 3.8 , 1.1, 0.33 and 0.1 nmol, dilution series were prepared separately before analysis at the level of 100-fold dilution of the mother liquor in DMSO by serial dilutions of 1: 3.4) in duplicate values for each concentration, and Then the values of U were calculated by the four-parameter logistic equation using the intralaboratory program software support.

3. Test for proliferation.

Cultured tumor cells (Cheka, human cervical tumor cells, ATCC CCB-2; Ν0-Η460, human non-small cell lung carcinoma cells, ATCC NTV-177; A2780, human ovarian carcinoma cells, ECACC # 93112519; Όυ 145, non-independent carcinoma cells human glands, ATCC NTV-81; ΗοΕα-ΜαΤιι-ΛΩΒ, cells of a multiresistant carcinoma of the human cervix, EPO-Ot Veg1sh; Caco-2, human colorectal carcinoma cells, ATCC NTV-37; B16P10, mouse melanoma cells, ATCC SK, ATCC 6475) were seeded at a density of 5000 cells per well (Όυ145, Ηе ^ а-ΜаΤи-А ^ K), 3000 cells per well (Ν0-Η460, OTEA), 2500 cells per well (A2780), 1500 cells per well (Caco-2) or 1000 cells per well (B16P10) in a 96-well microtiter plate in 200 μl in an appropriate growth medium supplemented with 10% fetal calf serum. After 24 hours, cells in one plate (zero plate) were stained with crystalline violet dye (see below), while the medium in other plates was replaced with fresh cultivation medium (200 μl), to which test substances were added at various concentrations (0 μmol, as well as in the range of 0.01-30 μmol; the final concentration of dimethyl sulfoxide solvent is 0.5%). Cells were incubated for 4 days in the presence of test substances. Cell proliferation was determined by staining the cells with a crystal violet dye: the cells were fixed by adding 20 μl / measurement point of an 11% glutaraldehyde solution for 15 min at room temperature. After three cycles of washing the cells with water, the plates were dried at room temperature. Cells were stained by adding 100 μl / measurement point of 0.1% crystalline violet dye solution (pH 3.0). After three cycles of washing the stained cells with water, the plates were dried at room temperature. The dye was diluted by adding 100 μl / measurement point of 10% acetic acid solution. The extinction was determined by photometry at a wavelength of 595 nm. The percentage change in the number of cells was calculated by normalizing the measured values to extinction values for the zero plate (= 0%) and extinction for untreated (0 μm) cells (= 100%). Values of GS50 (concentration of half-maximum inhibition) were determined by a four-parameter logistic equation.

Non-adherent MOBM-13 cells of acute human myelocytic leukemia (Ό8ΜΖ ACC 554) were seeded at a density of 5000 cells per well in a 96-well microtiter plate in 100 μl of growth medium supplemented with 10% fetal calf serum. After 24 hours, cell viability was determined in one plate using Ce11 Tbge-O1o Eipepex Ce11 νίαόίΐίΐν Akkau (Rgoteda), while 50 μl of medium containing the test compound was added to wells in other plates (final concentrations in the range of 0.001-10 μmol and control groups with IM8O; final concentration of solvent, dimethyl sulfoxide — 0.5%). Cell viability was determined after 72 hours using Ce11 TIGe-O1o dextrose Ce11 Maabbu Akkau (Rgoteda). The values of »» (half-maximal inhibition concentration) were determined by a four-parameter logistic equation using measurement data, which were normalized to cells treated with the carrier (IM8O) (= 100%) and measurement results immediately before exposure to the compound (= 0%).

4. Analysis of equilibrium solubility in a shake flask.

4a. Thermodynamic solubility in water.

The thermodynamic solubility of compounds in water was determined by analyzing the equilibrium solubility in a shake flask (see, for example, E.N. Kegpk, L. Όί: Igid-Nke Rgoregyek: SopserK 81gis1ige Iyppb Mebubk, 276-286, Vig1shd1op, MA, Akabepis , 2008). A saturated solution of the preparation was prepared and the solution was stirred for 24 hours to ensure equilibrium. To remove the insoluble fraction, the solution was centrifuged and the concentration of the compound in the solution was determined using a standard calibration curve. To obtain a sample in a 4 ml vial, 2 mg of the solid was weighed. Added 1 ml of phosphate buffer, pH 6.5. The suspension was stirred for 24 hours at room temperature. Then the solution was centrifuged. To obtain a sample for reference calibration, 2 mg of a solid sample was dissolved in 30 ml of acetonitrile. After sonification, the solution was diluted with water to 50 ml. Quantification for samples and standards was carried out by HPLC with UV detection. Two volumes of administration (5 and 50 μl) were made in triplicate for each sample. Three volumes of administration (5, 10 and 20 μl) were made for the reference.

- 48 027226

Chromatographic conditions:

HPLC column:

The volume of the injected sample:

Flow rate: mobile phase:

UV detector:

X1egga Μδ C18 2.5 μm 4.6 x 30 mm Sample: 3x5 μl and 3x50 μl μm

Reference: 5 μl, 10 μl, 20 μl 1.5 ml / min.

acid gradient:

A: Water / 0.01% TPA

B: Acetonitrile / 0.01% TPA min. - + 95% A 5% B

0-3 min-A 35% A 65% B, linear gradient 3-5 min-A 35% A 65% B, isocratic mode 5-6 min-A 95% A 5% B, isocratic mode wavelength - approximately maximum absorption (in the range of 200 and 400 nm)

Determination of the injection area of the sample and the standard, as well as the calculation of the solubility value (in mg / l), were carried out using software for HPLC (Aa1eg5 Etromeg 2 RK).

4b. Thermodynamic solubility in citrate buffer pH 4.

The thermodynamic solubility in water was determined by the method of analysis of equilibrium solubility in a shake flask [see EMAGO Η. Kegpps apy Ι Ι) ι (2008) 8O1iU1yu MeShoyz ΐη: Aegid-yke Rörgeyes: Sopser1z, 81gis1ige Ee51dp apy MeShoyz, p276-286. Vig1shd1op, MA: Asayetu Rgezz].

A saturated solution of the preparation was prepared and the solution was stirred for 24 hours to ensure equilibrium. To remove the insoluble fraction, the solution was centrifuged and the concentration of the compound in the solution was determined using a standard calibration curve.

To obtain a sample in a vial with a volume of 4 ml weighed 1.5 mg of the solid compound. Added 1 ml of citrate buffer, pH 4. The suspension was placed in a stirrer and stirred for 24 hours at room temperature. Then the solution was centrifuged. To obtain a sample for reference calibration, 0.6 mg of a solid sample was dissolved in 19 ml of a 1: 1 acetonitrile / water mixture. After sonification, the solution was supplemented with a mixture of acetonitrile / water 1: 1 to 20 ml.

Quantification for samples and standards was carried out by HPLC with UV detection. Two volumes of administration (5 and 50 μl) were made in triplicate for each sample. Three volumes of administration were made for the reference (5 μl, 10 μl and 20 μl).

Chemical substances:

citrate buffer, pH 4 (MEKSK Ag1. 109435; 1 liter of buffer consists of 11.768 g of citric acid, 4.480 g of sodium hydroxide, 1.604 g of hydrogen chloride)

Chromatographic conditions were as follows:

HPLC column: X1sgga Μδ C18 2.5 μm 4.6 x 30 mm

Sample Volume: Sample: 3x5 μl and 3x50 μl

Reference: 5 μl, 10 μl, 20 μl

Flow rate: mobile phase:

UV detector:

1.5 ml / min. acid gradient:

A: Water / 0.01% TPA

B: Acetonitrile / 0.01% TPA 0 min .: 95% A 5% B

0-3 min .: 35% A 65% B, linear gradient

3-5 min.: 35% A 65% B, isocratic mode

5-6 min .: 95% A 5% B, isocratic mode wavelength - approximately maximum absorption (in the range of 200 and 400 nm)

Determination of the injection area of the sample and the standard, as well as the calculation of the solubility value (in mg / l), were carried out using software for HPLC (Aa1eg5 Etromeg 2 RK).

Determination of the injection area of the sample and the standard, as well as the calculation of the solubility value (in mg / l), were carried out using software for HPLC (Aa1eg5 Etromeg 2 RK).

5. The permeability test in Saso-2.

Saso-2 cells (purchased from Computer /, Braunschweig, Germany) were seeded at a density of 4.5x10 ⁴ cells per well in 24-well insert plates, pore size 0.4 μm, and grown for 15 days in

- 49 027226 medium ΌΜΕΜ with the addition of 10% fetal bovine serum, 1% О1и! АМЛХ (100х, ОШСО), 100 units / ml penicillin, 100 μg / ml streptomycin (OGVSO) and 1% non-essential amino acids (100x). Cell storage occurred at a temperature of 37 ° C in a humidified atmosphere of 5% CO ₂ . The environment was changed every 2-3 days. Before conducting a permeability test, the culture medium was replaced by HEPES carbonate transfer buffer not containing fetal bovine serum (pH 7.2). To assess the integrity of the monolayer, transepithelial resistance (TEEEK) was measured. Test compounds were pre-dissolved in IM8O and added to the apical or basal-lateral section at a final concentration of 2 μmol in transfer buffer. Before they were incubated for 2 hours at 37 ° C, and after that, the cells were taken from both departments. The analysis of the content of the compounds was carried out after precipitation using methanol by LC / MS / MS. Permeability (Rarr) was calculated in the direction from the apical to the basal-lateral (A> B) and from the basal-lateral to the apical (B> A). The effective magnetic permeability was calculated using the following equation:

Rarr = (Ug / Po) (1/3) (P2 / 1) where Ug is the volume of the medium in the acceptor section, Po is the measured area or peak height of the test substance in the donor section at ΐ = ο, 8 is the surface area of the monolayer, P2 - the measured peak area of the test substance in the acceptor section after 2 hours of incubation, and ΐ is the incubation time.

The efflux coefficient from the basal lateral (B) to the apical (A) was calculated by dividing Papr B-A by A-B. In addition, the elimination of the compound was calculated. The following reference preparations were used to determine the permeability class: antipyrine, pyrazosin, verapamil, fluvastatin, cimetidine, ranitidine, atenolol, sulfasalazine.

6. Test for inhibition of carbonic anhydrase.

The principle of analysis is based on the hydrolysis of 4-nitrophenyl acetate with the use of carbonic anhydrase (Roskeg & 8 Schpe, Vyuset18yu, 1967, 6, 668), followed by photometric determination of the staining product, 4-nitrophenolate at 400 nm using a 96-channel spectrophotometer.

μl of test compounds dissolved in IM8O (100-fold final concentration), in a concentration range of 0.03-10 µmol / L (final), was pipetted in four parallel assays into the wells of a 96-well microtiter plate. Wells containing solvent without test compounds were used for control values [1) wells containing no carbonic anhydrase were used to correct non-enzymatic hydrolysis of the substrate, and 2) wells containing carbonic anhydrase were used to determine the activity of non-inhibited enzyme].

188 μl of test buffer (10 mmol / L Τπδ / ΗΟ, ρΗ 7.4, 80 mmol / L IaS1), with 3 units / per well of carbonic anhydrase-1 or without it [= human carbonic anhydrase-1 (81dta, # С4396)] for for determining inhibition of carbonic anhydrase-1 or 3 units / per well of carbonic anhydrase-2 or without it [= human carbonic anhydrase-2 (81dta, # C6165)] to measure the inhibition of carbonic anhydrase-2, was pipetted into the wells of a microtiter plate. The enzyme reaction was initiated by adding 10 μl of a substrate solution (1 mmol / L 4-nitrophenyl acetate (Pica # 4602) dissolved in anhydrous acetonitrile (final substrate concentration: 50 μmol / L). The plate was incubated at room temperature for 15 minutes. Absorption was determined by photometry at a wavelength of 400 nm. Inhibition of the enzyme was calculated after the measurement data were normalized to the absorption of reactions in wells without an enzyme (= 100% inhibition) and to the absorption of reactions in wells with an enzyme without an inhibitor (= 0% inhibition). elichiny U ₅₀ measured four parameter logistic equation using a proprietary software company.

Production Examples

Synthesis of compounds.

The synthesis of 5-fluoro-N- (pyridin-2-yl) pyridin-2-amine derivatives of formula (I) in accordance with the present invention is preferably carried out in accordance with the general synthesis sequences shown in schemes 1-6.

In addition to the methods described below, other methods may also be used to synthesize the target compounds, in accordance with the general knowledge of one skilled in the art of organic chemistry. The transformation order, given as an example in the following schemes, does not limit the scope of the present invention, and the corresponding synthesis steps from various schemes can be combined to obtain additional synthesis sequences. In addition, before and / or after the exemplary transformations, any of the substituents K ¹ , K ² , K ³ , K ⁴ and / or K ⁵ can be interconverted. These modifications may include modifications such as the introduction of protective groups, the cleavage of protective groups, the reduction or oxidation of functional groups, halogenation, metallization, coupling reactions with catalysis on metal, substitution or other reactions known to those skilled in the art. Such transformations include transformations that bring functionality that allows further interconversion of substituents. The corresponding protective groups, as well as the methods of their introduction and cleavage are well known to specialists (see, for example, Τ.Υ. Ogeepe apy R.O.M. \ Υιιΐ3 ίη P ^ οΐесΐ ^ νе Огоирз ίη Ogdats 8up 50 027226

1Jech + 3rd Edition, Shpeu 1999). Specific examples are described in the sections that follow. Also, as is known to those skilled in the art, it is possible for two or more consecutive steps to be carried out without processing data between steps, for example, as a reaction in a single reaction vessel.

The geometry of the sulfoximine group shows that the compounds of general formula (I) are chiral. The separation of racemic sulfoximines into enantiomers can be carried out using methods known to those skilled in the art, preferably using preparative HPLC on a chiral stationary phase.

Scheme 1 shows a preferred approach to the synthesis of compounds of general formula (I). At the first stage, 2-chloro-5-fluoro-4-iodopyridine (1; No. SL8 884494-49-9) reacts with the boronic acid derivative K ² -B (OK) 2 of formula (2), where K ² has the meaning as defined for a compound of general formula (I) to give a compound of formula (3). The boronic acid derivative (2) may be boronic acid (K = —H) or a boronic acid ester, for example, isopropyl ester of boronic acid (K = —CH (SS) 2), preferably an ester derived from pinacol, where the intermediate is boronic acid forms 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (Kk-sssch-sssch-).

The catalysts in the coupling reaction are palladium catalysts, for example, Ρά (0) catalysts such as (tetrakis- (triphenylphosphine) palladium (0) [Pb (PPI ₃ ) ₄ ], tris- (dibenzylideneacetone) dipalladium (0) [Pb ₂ ( ba) ₃ ], or Ρά (Π) catalysts, such as dichloro-bis- (triphenylphosphine) -palladium (P) [Pb (RRI ₃ ) ₂ Cl ₂ ], palladium (II) acetate and triphenylphosphine or [1,1 ' bis- (diphenylphosphino) ferrocene] palladium dichloride.

Preferably, the reaction is carried out in a solvent mixture, such as 1,2-dimethoxyethane, dioxane, DMF, DME, THF or isopropanol with water and in the presence of a base such as potassium carbonate, sodium bicarbonate or potassium phosphate (see Ό.Θ. W11, Vogoshs Άώάδ, 2005 Sh.P.GU-US11 Ueg1a§ Oshi & Co. KOAA, ShetIepp, ΚΒΝ 3-527-30991-8 and the references cited in this document).

- 51 027226

The reaction takes place at temperatures ranging from room temperature (i.e., approximately 20 ° C.) to the boiling point of the corresponding solvent. In addition, the reaction can be carried out at temperatures above the boiling point using high pressure pipes and a high frequency furnace.

The reaction is preferably completed after 1-36 hours of reaction time.

In a second step, the compound of formula (3) is reacted with the corresponding pyridin-2amine of formula (4), wherein K ¹ , K ³ and K ⁴ are as defined for the compound of general formula (I) to give a compound of formula (5) . This coupling reaction can be carried out by the palladium-catalyzed C-Ν cross-coupling reaction (a review of C-росс cross-coupling reactions is given, for example, in a) b. Lapd 8.b. VISETSH ίη Me1a1-Ca1a1u / e0 Сgo88-Soir1shd KeasEopv, 2nd ed.: Α. Be Meuege, R. O1e0epse Ехх: \ UPeu-USS: Weinheim, Germany, 2004).

Preferred is the use of tris (dibenzylideneacetone) dipalladium (0), (9,9-dimethyl-9H-xanthene-4,5-diyl) -bis- (diphenylphosphane) and cesium carbonate in dioxane as described herein. These reactions are preferably carried out in an argon atmosphere for 3-48 hours at 100 ° C in a high-frequency furnace or in an oil bath.

In the third step, as a result of the imination of the compound of formula (5), the corresponding sulfilimine of formula (6) is obtained (see, for example, a) C. A1., Ogdasch Leyegv, 2004, 6, 1305; B) ί. Khideg e! A1., VO 2012/038411). Said amination is preferably carried out by reacting a compound of formula (5) with trifluoroacetamide and an appropriate oxidizing agent, such as 1,3-dibromo-5,5-dimethylhydantoin, in the presence of an alkali metal salt of tert-butanol, such as sodium tert-butanol, in cyclic ether, such as tetrahydrofuran and dioxane, or mixtures thereof, as a solvent.

The oxidation of sulfylimine of formula (6), followed by deprotection of the trifluoroacetyl group, yields Ν-unprotected sulfoximine of formula (I) (K ⁵ = H) (see, for example, a) Α. P1aSh e! A1., VO 2006/037945; B) ί. Khideg e! A1., VO 2012/038411). Said oxidation is preferably carried out by reacting the compounds of formula (6) with an alkali metal salt of manganese acid, such as potassium permanganate, in an aliphatic ketone of the formula C ₁ -C ₂ -C (O) -C ₁ -C ₂ -alkyl, such as acetone, as a solvent. If the trifluoroacetyl group present in the compounds of formula (6) does not split during the above oxidation process, the removal of the trifluoroacetyl group can be carried out by treating the resulting intermediate with an appropriate base, such as an alkali or alkaline earth metal carbonate, preferably potassium carbonate, in the corresponding alcohol, such as an aliphatic alcohol _C1-C6 alkyl-OH, preferably methanol. Said oxidation is preferably carried out by reacting the compounds of formula (6) with a peroxomonosulphate-based oxidizing agent, such as Ohope® (SL8 No. 37222-66-5), in a mixture of an appropriate solvent, such as methanol / water and, if necessary, an additional ΌΜΡ while adjusting the pH of the reaction mixture using an aqueous solution of potassium hydroxide to obtain Ν-unprotected sulfoximine of the formula (I) (K ⁵ = H).

Pyridin-2-amines of the formula (4) are in some cases commercially available or can be obtained by methods known to a person skilled in the art, for example, from the corresponding 4-hydroxymethyl-pyridin-2-amine by converting the hydroxy group contained therein to an appropriate leaving group, for example, chlorine or bromine, followed by nucleophilic substitution using a thiol of general formula K ¹ -8H, where K ¹ is as defined for the compound of general formula (I). If necessary, the amino group present in said 4-hydroxymethylpyridin-2-amine can be protected with an appropriate protecting group. Protective groups for amino groups present in analogues and methods for their introduction and removal are well known to those skilled in the art, see, for example, Έν. Oheepe apb R.S.M. \ Uii> w: Rgo! Ees! Her Sogirv sh Ogdashs 8up! Her 818, 3rd edition, \ UPeu (1999). Thiols of the formula P'-8H are known to the person skilled in the art and are commercially available in a wide range.

Ν-unprotected sulfoximines of the formula (I) (K ⁵ = H) can react to produce Ν functionalized derivatives of the formula (I). There are many methods for producing Νfunctionalized sulfoximines by functionalizing the nitrogen of the sulfoximine group:

alkylation: see, for example, a) and. Liskd e! A1., I8 2007/0232632; B) S.K. 1bn8op, I. Ogd. Sows. 1993, 58, 1922; c) C. Voit e! A1., Zuhjejaz 2009, 10, 1601;

acylation: see, for example, a) C. Voit e! A1., Sows. Egor. I. 2004, 10, 2942; B) C. Voit e! A1., 8U1E818 2002, 7, 879; c) C. Voit e! A1., Sows. Egor. I. 2001, 7, 1118;

arylation: see, for example, a) C. Voit e! A1., Those !. Be !!. 1998, 39, 5731; B) C. Voit e! A1., I. Ogd. Sows. 2000, 65, 169; c) C. Voit e! A1., 8Up! Her 515 2000, 7, 911; ά) C. Voit e! A1., I. Ogd. Sows. 2005, 70, 2346; e) and. Liskd e! A1., VO 2007/71455;

reaction with isocyanates: see, for example, a) V.! Waieg e! A1., I. Ogd. Sows. 1966, 31, 3440; B) S.K.

1Npvop e! A1., I. Vol. Sows. 8os. 1970, 92, 6594; c) 8. Л11еηта ^ к е! a1., Α ^ SEet. 8sapb. 8th In 1983, 325;

ά) and. Liskd e! A1., I82007 / 0191393;

reaction with sulfonyl chlorides: see, for example, a) Ό.Ι Сgat e! A1., I. Vol. Sows. 8os. 1970, 92, 7369;

- 52 027226

B) S.K. ΙοΗηδοη e! A1., I. Ogd. Siet. 1978, 43, 4136; c) A.S. Wagpez, I. Honey. Siet. 1979, 22, 418; ά) I). Sgshd e! A1., Those !. 1995, 51, 6071; e) and. yiskshd e! A1., I82007 / 191393;

reaction with chloroformates: see, for example, a) R.V. Kyu e! A1., ΏΕ2129678; B) J.Y. A1., I. At.

Siet. 8os. 1974, 96, 2183; c) P. 8! θδδ e! A1., Siet. Veg. 1978, 111, 1453; ά) and. yiskshd e! A1.,% O

2005/37800;

reaction with cyanogen bromide: see, for example, a) J.T. 8aeg e! A1., Bogdats Syetz! Gu 1972, 11, 238; B) C. Voit e! A1., Ogd. Bay. 2007, 9, 2951; c) and. yiskshd e! A1.,% O 2011/29537.

An alternative approach to the synthesis of 5-fluoro-N- (pyridin-2-yl) pyridin-2-amine derivatives of formula (I) in accordance with the present invention is described in Scheme 2.

In a first step, a compound of formula (3), wherein K ² is as defined for a compound of general formula (I), is reacted with the corresponding pyridin-2-amine of formula (7), where K ³ and K ⁴ are as defined for a compound of general formula (I) to give a compound of formula (8). This coupling reaction can be carried out by the palladium-catalyzed C-рос cross-coupling reaction (a review of C-Ν cross-coupling reactions is given, for example, in a) d. Lapd 8.Y. Visimai ίη Me! A1-Ca! A1u / eb Sgo88-Soir1td Keasyopz, 2nd ed.: A. de Meuege, R. P1ebepsy, Εάδ .: SPeu-USN: Weinheim, Germany, 2004).

Preferred is the use of tris (dibenzylideneacetone) dipalladium (0), (9,9-dimethyl-9H-xanthene-4,5-diyl) -bis- (diphenylphosphane) and cesium carbonate in dioxane as described herein. These reactions are preferably carried out in an argon atmosphere for 3-48 hours at 100 ° C in a high-frequency furnace or in an oil bath.

Pyridin-2-amines of the formula (7) are in some cases commercially available or can be obtained by methods known to the person skilled in the art, for example, by reduction of the corresponding carboxylic acids or their esters.

In a second step, a compound of formula (8), wherein K ² , K ³ and K ⁴ are as defined for a compound of general formula (I), is converted to a compound of formula (9), where K ² , K ³ and K ⁴ are as defined for the compound of general formula (I), and wherein YO is a leaving group, preferably chloro or bromo. Preferred is the use of thionyl chloride as described herein in NMR or 1) MP and YMS for the formation of benzyl chloride derivatives (Y0 = C1). The formation of benzyl chloride derivatives (JO = Br) can be carried out using tetrabromomethane and triphenylphosphane in YSM (see, for example, Po11a e! A1., Vyuudashs apt Meb1ssa1 Syet1z! Gu, 2004, 12, 1151).

In a third step, the compound of formula (9) is converted to a thioether of formula (5), where K ¹ , K ² , K ³ and K ⁴ are as defined for the compound of general formula (I) by reaction with an appropriate thiol of formula K ² 8H , where K ¹ has the meaning, as defined for the compound of general formula (I), under basic conditions, to obtain the corresponding thioether of formula (5) (see, for example, 8 attopd e! a1., Vyuogd. Medical Set. Ye !!. 2005, 15, 3519). Thiols of the formula K ^ 8H are known to the person skilled in the art and are commercially available in a wide range.

In the final steps, the thioether of formula (5) is converted to the corresponding sulfoximine of formula (I) as described in Scheme 1.

- 53 027226

Another alternative approach to the synthesis of 5-fluoro-N- (pyridin-2-yl) pyridin-2-amine derivatives of formula (I) in accordance with the present invention is described in Scheme 3.

Scheme 3

In a first step, the compound of formula (3), wherein K ² is as defined for the compound of general formula (I), is converted to the 5-fluoro-pyridin-2-amine of formula (10). This reaction can be carried out by the palladium-catalyzed C-реакции cross-coupling reaction (a review of C-росс cross-coupling reactions is given, for example, in a) b. Lapd, δ.Η VPSN \ uak1 sh Me1a1-Sa1a1u7ey Sgozz-SoirNpd Keasyopz, 2nd ed .: A. 1e Meuege, E. O1eyeps, Euse: \\ 'Peu - \' C11: Weinheim, Germany, 2004) .

Preferred is the use of lithium bis (trimethylsilyl) amide, tris- (dibenzylideneacetone) dipalladium (0) and 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′triisopropylbiphenyl in THE as described herein. These reactions are preferably carried out in an argon atmosphere for 3-24 hours at 60 ° C in an oil bath.

In a second step, the compound of formula (10) reacts with the corresponding pyridine derivative of formula (11), wherein K ¹ , K ³ and K ⁴ are as defined for the compound of general formula (I), and where bC is a leaving group, preferably chlorine, to give a compound of formula (5). This coupling reaction can be carried out by the palladium-catalyzed C-рос cross-coupling reaction (a review of the C-Ν cross-coupling reactions is given, for example, in a) K. Lapd, δ.Η HPSN \ ua1 w Me1a1-Ca1a1u7ey Sgozz-SoirNpd Keascopes, 2- e ed .: A. 1e Meuege, E. [DeskspsN, Eiz .: \ UPeu- \ 'C11: Weinheim, Germany, 2004).

Preferred is the use of tris (dibenzylideneacetone) dipalladium (0), (9,9-dimethyl-9H-xanthene-4,5-diyl) -bis- (diphenylphosphane) and cesium carbonate in dioxane as described herein. These reactions are preferably carried out in an argon atmosphere for 3-48 hours at 100 ° C in a high-frequency furnace or in an oil bath. Also preferred is the use of chlorine (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′biphenyl) [2- (2-aminoethyl) phenyl] palladium (P) methyl tert- butyl ether adduct, 2 (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl and potassium phosphate in toluene and NMΡ. These reactions are preferably carried out in an argon atmosphere for 2-24 hours at 100-130 ° C in a high-frequency furnace or in an oil bath.

In the final steps, the thioether of formula (5) is converted to the corresponding sulfoximine of formula (I) as described in Scheme 1.

The pyridine derivatives of formula (11) can be obtained in accordance with methods known to a person skilled in the art, for example, by converting a halogenmethyl group to a thioether present in a compound of formula (11) using a thiol of formula K ³ -8H, where K ¹ has the meaning is defined for the compound of general formula (I) in a manner analogous to the method described above for the pyridinamines of formula (4) and for the conversion of intermediates (9) to thioesters of formula (5) in Scheme 2. These halogenomethylpyridine precursors are known to those skilled in the art and in some cases are commercially available.

Another alternative approach to the synthesis of 5-fluoro-N- (pyridin-2-yl) pyridin-2-amine derivatives of formula (I) in accordance with the present invention is described in Scheme 4.

In a first step, a compound of formula (10), wherein K ² is as defined for a compound of general formula (I), is reacted with the corresponding pyridine derivative of formula (12), where

- 54 027226

K ³ and K ⁴ are as defined for the compound of general formula (I), and wherein BO is a leaving group, preferably chloro, to give a compound of formula (8). This coupling reaction can be carried out by the palladium-catalyzed C-Ν cross-coupling reaction (a review of C-Ν cross-coupling reactions is given, for example, in a) B. Bapd, 8. B. VisN \\ a1c1 t Me! A1-Ca! A1u7eb Sgozz-SoirBpd

KeasBopz, 2nd ed .: A. Be Meuege, B. B1ebepsB, Ebz: A’Peu-USN: Weinheim, Germany, 2004).

Preferred is the use of chlorine (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) - [2- (2-aminoethyl) phenyl] palladium (P) methyl tert-butyl ether adduct described in 2 - (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl and potassium phosphate in toluene and ΝΜΡ. These reactions are preferably carried out in an argon atmosphere for 2-24 hours at 100-130 ° C in a high-frequency furnace or in an oil bath.

In subsequent steps, the benzyl alcohol of formula (8) is first converted to the corresponding thioether of formula (5) as described in Scheme 2, and then converted to the corresponding sulfoximine of formula (I) as described in Scheme 1.

The pyridine derivatives of formula (12) are known to those skilled in the art and are commercially available in a wide range.

Another alternative approach to the synthesis of 5-fluoro-N- (pyridin-2-yl) pyridin-2-amine derivatives of formula (I) in accordance with the present invention is described in Scheme 5.

Scheme 5

formula (I), B ⁵ = N

In a first step, a thioether of formula (11), wherein K ¹ , K ³ and K ⁴ are as defined for compounds of formula (I), and where BO is a leaving group, preferably chloro, is oxidized to give the corresponding sulfoxide of formula (13). There are several methods for the oxidation of thioether to obtain the corresponding sulfoxide (see, for example, (a) M.N. AN e! A1., 8up £ Bez13 1997, 764; (b) M.S. Saggepo, Sbet. Keu. 1995, 95, 1717; (c) I. Ra! E1 e! A1., Ogd. Proc. Kez. Beu. 2002, 6, 225; (b) Ν. Kiag e! A1., Sat. Keu. 2003, 103, 3651). Preferred is the use of iodic acid and ferric chloride (III) described herein.

At the second stage, as a result of the rhodium-catalyzed amination of the sulfoxide of the formula (13), the corresponding sulfoximine of the formula (14) is obtained (see, for example, B0t e! A1., Ohd. Be !!. 2004, 6, 1305).

In a third step, a compound of formula (10), wherein K ² is as defined for a compound of general formula (I), is reacted with sulfoximine (14) to give unprotected sulfoximine of formula (I) (K ⁵ = H). This coupling reaction can be carried out by the palladium-catalyzed C--cross-coupling reaction (a review of C-Ν cross-coupling reactions is given, for example, in a) B. Bapd, 8.B. VisB ^ a1b t Me! A1-Ca! A1u7eb Sgozz-Soir1td KeasBopz, 2nd ed.: A. Be Meuege, B. BhebepsB, Ebz .: A'Peu-USN: Weinheim, Germany, 2004).

Preferred is the use of chlorine (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2-aminoethyl) phenyl] palladium (P) methyl tert-butyl ether adduct, 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl and potassium phosphate in toluene and NMΡ. These reactions are preferably carried out in an argon atmosphere for 1-24 hours at 100-130 ° C in a high-frequency furnace or in an oil bath.

Another alternative approach to the synthesis of 5-fluoro-N- (pyridin-2-yl) pyridin-2-amine derivatives

- 55 027226 of the formula (I) in accordance with the present invention is described in scheme 6.

In a first step, a sulfoxide of formula (13), wherein K ¹ , K ³ and K ⁴ are as defined for compounds of formula (I), and where 'TO means a leaving group, preferably chlorine, is converted to unprotected sulfoximine of formula (15) by rhodium-catalyzed immunization, followed by deprotection under basic conditions (see, for example, BOt e! a1., Ogd. Rey. 2004, 6, 1305).

In the second step, unprotected sulfoximine of formula (15), where K ¹ , K ³ and K ⁴ are as defined for compounds of formula (I), is converted to protected sulfoximine of formula (16) by reaction with ethyl chloroformate in pyridine (see, e.g. a) R.V. Ktu e! A1., ΏΕ2129678; B) Ώ.Ι. Sgat e! A1., I. At. Eat. 8os. 1974, 96, 2183; c) R. 8! §§ e! A1., eat. Veg. 1978, 111, 1453; b) and. Rnsksd e! A1., JSC 2005/37800).

Scheme 6

general formula (I), reacts with sulfoximine (16) to give a protected sulfoximine of formula (I) (K ⁵ = C (O) OE!). This coupling reaction can be carried out by the palladium-catalyzed cross-coupling reaction CX (a review of the cross-coupling reactions CX is given, for example, in a) R. Lapd, 8.Ώ. Bibliography a1b ΐη Me! A1-Ca! A1u7eb Sog§§-Soir1td Keas! Jupp§, 2nd ed.: A. Be Meuege, R. E1ebeps, Eb§ .: APeu-USN: Weinheim, Germany, 2004) .

Preferred is the use of chlorine (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1, G-biphenyl) [2- (2-aminoethyl) phenyl] palladium (P) methyl tert-butyl ether adduct, 2- ( dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl and potassium phosphate in toluene and ChMR. These reactions are preferably carried out in an argon atmosphere for 1-24 hours at 100-130 ° C in a high-frequency furnace or in an oil bath.

At the last stage, the protected sulfoximine of the formula (I) (K ⁵ = C (O) OE!) Is converted to the unprotected sulfoximine of the formula (I) (K ⁵ = H) by reaction with an alkali metal salt of an aliphatic alcohol of the formula C ₁ -C ₄ -alkyl -OH in the corresponding aliphatic alcohol. Preferred is the use of sodium ethoxide as described herein in ethanol a! 60 ° C.

Getting connections

The sections below that describe chemicals and the Examples section use the following abbreviations:

Bg (wide); СОС1 ₃ (deuterated chloroform); cNex (cyclohexane); b (doublet); bb (doublet of doublets); b! g (doublet of triplets); OSM (dichloromethane); O! REA (diisopropylethylamine); ΏΜΕ (1,2-dimethoxyethane); ΏΜΓ (X, X-dimethylformamide); OM8O (dimethyl sulfoxide); ec (equivalent); E8 (electrospray); E! OAc (ethyl acetate); E! OH (ethanol); 1RgON (isopropanol); tCPBA (metachloroperoxybenzoic acid), MeCX (acetonitrile), MeOH (methanol); M8 (mass spectrometry); HMP (X-methylpyrrolidin-2-one); \ B8 (X-bromosuccinimide), KMK (nuclear magnetic resonance); Okope® (triple salt 2KN8O ₅ -KN8O ₄ -K ₂ 8O ₄ ); p (pentet); Rb (brr1) C1 ₂ ([complex 1,1'-bis-56 027226 (diphenylphosphino) ferrocene] dichloropalladium (P) with dichloromethane); ς (quartet); CT (room temperature); § (singlet); per!. ac (saturated water); 8U ₂ (silica gel); TPA (trifluoroacetic acid);

TPAA (trifluoroacetic anhydride), THP (tetrahydrofuran); ! g (triplet); Ιιτί (triplet of doublets).

The IUPAC names in the Examples section were built using the program

ASRZhate, version 12.01 of the company ASR RAV8.

Example 1: (gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) J- {4 - [(8-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine

A sample containing 2-chloro-5-fluoro-4-iodopyridine (1000 mg; 3.88 mmol; APAC Pagantasei Pca1, PPC), (4-fluoro-2-methoxyphenyl) boronic acid (660 mg; 3.88 mmol; APSi Cet1ca1 Sotrapu Sch.) and tetrakis- (triphenylphosphine) palladium (0) (449 mg; 0.38 mmol) in 1,2-dimethoxyethane (10.0 ml) and 2 mol of an aqueous solution of potassium carbonate (5.8 ml), degassed using argon. The sample was stirred under argon for 4 hours at 100 ° C. After cooling, the sample was diluted with ethyl acetate and THP and washed with a saturated aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified using column chromatography (hexane to hexane / ethyl acetate 50%) to obtain the desired product (947 mg; 3.70 mmol).

¹ N NMK (400 MN /, СРС1 ₃ , 300К) δ = 8.27 (t, 1Н), 7.33 (t, 1Н), 7.24 (t, 1Н), 6.75 (t, 2Н), 3.83 (§,

3H).

Preparation of Intermediate 1.2: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) Ж- {4 [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine

Sample containing 2-chloro-5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridine (400 mg; 1.57 mmol), 4 [(methylsulfanyl) methyl] pyridin-2-amine (483 mg; 3 , 13 mmol; ichrOr§8up! Be13 Ρΐά.), (9,9-dimethyl-9Hxanthen-4,5-diyl) -bis- (diphenylphosphane) (40 mg; 0.07 mmol) and cesium carbonate (765 mg; 2.35 mmol) in dioxane (6.0 ml), degassed using argon. In an argon atmosphere, Tris (dibenzylideneacetone) dipalladium (0) (21 mg; 0.02 mmol) was added, and the sample was stirred in a closed high-pressure pipe for 5 h at 100 ° C. After cooling, the sample was diluted with an aqueous sodium chloride solution and extracted with PCM (3x). The mixed organic phases were filtered using a Whatman filter and concentrated. The residue was purified using chromatography (hexane to hexane / ethyl acetate 30%) to obtain the desired product (556 mg; 1.48 mmol).

¹ H NMR (400 MH, CPC1 ₃ , 300K) δ = 8.15 (t, 2H), 7.61 (t, 1H), 7.40 (§, 1H), 7.35 (br, 1H), 7.29 (t, 1H), 6.82 (t, 1H), 6.75 (t, 2H), 3.83 (S, 3H), 3.62 (S, 2H), 2.03 (S, 3H).

Getting the final product.

Under argon, a solution of 2,2,2-trifluoroacetamide (195 mg; 1.73 mmol) in dioxane (0.5 ml) was added dropwise to a solution of sodium tert-butoxide (111 mg; 1.15 mmol) in dioxane (0 , 6 ml), so that the temperature of the mixture does not exceed 10 ° C. Then, a fresh solution of 1,3-dibromo-5,5-dimethylhydantoin (247 mg; 0.86 mmol) in dioxane (0.6 ml) / THP (1.0 ml) was added dropwise to the stirred mixture so that the temperature of the mixture did not exceed 10 ° C. Then the mixture was stirred for 10 min at 10 ° C. Finally, a solution of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) W {4 - [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine (430 mg; 1.15 mmol) in dioxane (1.0 ml), so that the temperature of the mixture does not exceed 10 ° C. The mixture was stirred for 60 min at 10 ° C. The sample was diluted with toluene (2.0 ml) under cooling and an aqueous solution of sodium sulfite (145 mg; 1.15 mmol in 2.0 ml of water) was added so that the temperature of the mixture did not exceed 15 ° C. An aqueous solution of sodium chloride was added and the sample was extracted using ethyl acetate (3x). The mixed organic phases were filtered using a Whatman filter and concentrated to give crude 2,2,2-trifluoro - - [[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino } pyridin-4yl) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide, which was used without further purification.

Acetone (6.0 ml) and potassium permanganate (814 mg; 5.15 mmol) were added to the residue, and the mixture was stirred at 50 ° C for 90 minutes. Additional potassium permanganate (223 mg; 1.42 mmol) was added and stirring was continued at 50 ° C for 4 hours. Finally, additional potassium permanganate (305 mg; 1.93 mmol) was added and stirring was continued at 50 ° C for 150 minutes After cooling, the sample was filtered, the residue was washed with acetone and the combined filtrates were concentrated.

The residue was dissolved in MeOH (60 ml), potassium carbonate (182 mg; 1.32 mmol) was added and the reaction mixture was stirred at room temperature for 20 minutes. The sample was diluted with an aqueous solution of sodium chloride and was extracted using an ESM (3x). The mixed organic phases were filtered using a Whatman filter and concentrated. To obtain the desired product (50 mg; 0.12 mmol), the residue was purified using preparative HPLC.

System: \ Wa1s1 + Au1origShsa1yup8u81et: Riter 254, 8atr1e Mapadeg 2767, SRO, ϋΑϋ 2996, 3100 Speaker: HVpdbe C18 5 μm 100x30 mm Solvent b: A = H ₂ O + 0.2% ΝΗ ₃ (32%) B = MeCI Gradient: 0-8 minutes 15-50% B Flow rate: 50 ml / min. Temperature: Room temperature

Solution: 132 mg / 2 ml EMR / Meon 1: 1 Volume entered samples: 2 x 1 ml Detection: DMD, scanning range 210-400 nm M8 Ε8Ι +, Ε8Ι-, scanning range 160-1000 τη / ζ Retention time: 3.39 - 3.88 min. M5 (E5 +): w / ζ = 404

¹ H NMR (400 MP /, a6-EMZO, 300K) δ = 9.80 (8, 1H), 8.20 (t, 1H), 8.16 (t, 1H), 7.79 (t, 1H), 7.59 (t, 1H) 7.34 (t, 1H), 7.09 (t, 1H), 6.91 (t, 2H), 4.36 (t, 2H), 3.80 (8, 3H), 3.72 (8, 1H), 2.88 (8, 3H).

Alternative Procedure for Preparing Intermediate 1.2: 5-fluoro-4- (4-fluoro-2methoxyphenyl) ^ - {4- [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine

Preparation of the intermediate yl] amino} pyridin-4-yl) methanol of the substance 1.3: (2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-

A sample containing 2-chloro-5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridine (411 mg; 1.61 mmol), (2aminopyridin-4-yl) methanol (200 mg; 1.61 mmol; ABSC OTN & CO. KO), (9,9-dimethyl-9H-xanthene-4,5diyl) -bis- (diphenylphosphane) (418 mg; 0.72 mmol) and cesium carbonate (784 mg; 2.41 mmol) in dioxane (8.0 ml), degassed using argon. In an argon atmosphere, Tris (dibenzylideneacetone) dipalladium (0) (147 mg; 0.16 mmol) was added and the sample was stirred for 29 hours at 100 ° C. After cooling, an additional amount of (2-aminopyridin-4-yl) methanol (100 mg; 0.81 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl) -bis- (diphenylphosphane) (118 mg; 0.20 mmol) and Tris (dibenzylideneacetone) dipalladium (0) (74 mg; 0.08 mmol) and the mixture was stirred for 19 h at 100 ° C. After cooling, the sample was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated. To obtain the desired product (389 mg; 1.13 mmol), the residue was purified by chromatography (ESM / JUN 9: 1).

¹ H NMR (400 MP /, and _6- EMZO, 300K) δ = 9.66 (8, 1H), 8.17 (t, 1H), 8.05 (t, 1H), 7.80 (t, 1H), 7.51 (8, 1H ), 7.31 (t, 1H), 7.06 (t, 1H), 6.88 (t, 1H), 6.75 (t, 1H), 5.31 (ίτ, 1H), 4.44 (ά, 2H), 3.76 (8, 3H) .

- 58 027226

Obtaining the final product (alternative procedure for the preparation of intermediate 1.2).

To a stirred solution of (2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methanol (350 mg; 1.01 mmol) in OSM (4, 0 ml) and ΝΜΡ (0.4 ml) at 0 ° C. thionyl chloride (0.19 ml; 2.55 mmol) was added dropwise. The mixture was stirred for 7 hours at room temperature. The sample was diluted with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and was extracted using OSM (3x). The mixed organic phases were filtered using a Whatman filter and concentrated to give crude N- [4- (chloromethyl) pyridin-2-yl] -5 fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine, which was used on the next step without further purification.

The residue was redissolved in ΕίΟΗ (12.0 ml) and the resulting solution was cooled to 0 ° C. Sodium methanethiolate (158 mg; 2.26 mmol) was added in portions to the stirred solution at 0 ° C. The mixture was stirred for 4 hours at room temperature, then it was diluted with OCM and washed with an aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated. To obtain the target product (301 mg; 0.81 mmol), the residue was purified by chromatography (OCM / 95: 5).

¹ H NMR (400 MI /, COS1 ₃ , 300K) δ = 8.15 (t, 2Η), 7.61 (t, 1Η), 7.40 (L, 2Η), 7.29 (t, 1Η), 6.82 (t, 1Η), 6.75 (t, 2Η), 3.83 (δ, 3Η), 3.62 (δ, 2Η), 2.03 (δ, 3Η).

An alternative cooking procedure according to example 1.

Preparation of Intermediate 1.4: (^ ac) -2,2,2-trifluoro-N - {[(2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} pyridine- 4-yl) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide

Under argon, a solution of 2,2,2-trifluoroacetamide (2.53 g; 22.4 mmol) in ΤΗΡ (10.0 ml) was added dropwise to a solution of sodium tert-butoxide (1.43 g; 14.9 mmol) in ΤΗΡ (12.0 ml), so that the temperature of the mixture does not exceed 10 ° C. Then, a fresh solution of 1,3-dibromo-5,5-dimethylhydantoin (3.20 g; 11.2 mmol) in ΤΗΡ (12.0 ml) was added dropwise to the stirred mixture, so that the temperature of the mixture did not exceed 10 ° C. . Then the mixture was stirred for 10 min at 10 ° C. Finally, a solution of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4 [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine was added dropwise to the stirred mixture (5, 57 g; 14.9 mmol; intermediate 1.2) in dioxane (12.0 ml), so that the temperature of the mixture does not exceed 10 ° C. The mixture was stirred for 60 min at 10 ° C. The sample was diluted with toluene (40.0 ml) under cooling and an aqueous solution of sodium sulfite (1.88 g; 14.9 mmol in 40.0 ml of water) was added so that the temperature of the mixture did not exceed 15 ° C. A sample was thrice (3x) extracted with ethyl acetate. The mixed organic layers were washed with an aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. To obtain the desired product (4.71 g; 9.72 mmol), the residue was purified using silica gel column chromatography (from OCM to OSM / ΕίΟΗ 95: 5).

¹ H NMR (400 MI /, COS1 ₃ , 300K) δ = 8.29 (t, 1Η), 8.18 (t, 1Η), 7.83 (δ, 1Η), 7.50 (bg, 1Η), 7.32 (t, 1Η), 7.28 (t, 1Η), 6.79 (t, 3Η), 4.52 (ά, 1Η), 4.21 (ά, 1Η), 3.85 (δ, 3Η), 2.71 (δ, 3Η).

Alternative production of the final product (example 1).

To a stirred solution of 2,2,2-trifluoro-N - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methyl] ( methyl) -X ⁴ -sulfanylidene} acetamide (4.64 g; 9.58 mmol) in OMI (350 ml), methanol (100 ml) and water (100 ml) was added dropwise an aqueous solution of potassium hydroxide (25%) to in order to adjust the pH to 10.5. Ο \ οικύ < ^: (5.00 g; 8.14 mmol) was added and the mixture was stirred at room temperature for 4.5 hours. During this time, the pH was adjusted in the range of 10-11, if necessary, added dropwise an aqueous solution of potassium hydroxide (25%). The mixture was filtered, and the filter cake was washed with a large amount of dichloromethane. The pH of the filtrate was adjusted to 6-7 using an aqueous solution of hydrogen chloride (15%). The filtrate was washed with an aqueous solution of sodium chloride and then with an aqueous solution of sodium thiosulfate (10%). When evaporating the solvents using a rotary evaporator, a solid was isolated from the solution by precipitation. The precipitated solid was isolated by suction filtration, washed with OCM and diisopropyl ether and dried to obtain the desired product (2.61 g; 6.43 mmol).

¹ H NMR (400 MI /, G-OM ^ C), 300K) δ = 9.82 (δ, 1Η), 8.21 (t, 1Η), 8.16 (t, 1Η), 7.78 (t, 1H), 7.59 (t , 1Η), 7.34 (t, 1Η), 7.09 (t, 1Η), 6.90 (t, 2Η), 4.35 (t, 2Η), 3.79 (δ, 3Η), 3.75 (δ, 1Η), 2.87 (δ, 3Η).

- 59 027226

Examples 2 and 3: enantiomers.

5-Fluoro-4- (4-fluoro-2-methoxyphenyl) -№- {4 - [(8-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin2-amine

(race) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -№- {4 - [(8-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine (3.47 g) was divided into single enantiomers by preparative chiral HPLC.

System: 8er1a1es: Rger ZRS100, Speaker: Sygafak 1C5 μm 250x30 mm Solvent: СО ₂ /2-ррорапо170 / 30 +0.4% ϋΕΑ Flow rate: 100 ml / min. Pressure (output) 150 bar Temperature: 40 ° C Solution: 3,468 β / 55 b OSM / MeOH 2: 1 Volume entered samples: 112xO, 49t Detection: UV, 254 nm. Time retention (in minutes) purity (%) exit specific optical rotation: Example 2 Enantiomer 1 7.0-8.1 99.15 1.31 g (3.24 mmol) [α] _ο ^2υ = 12.0 ° +/- 0.15 ° (ϋΜ3Ο, 589 psi, 20 ° C). Example 3 Enantiomer 2 8.5 - 10.5 96.98 1.32 § (3.26 mmol) [α] _ο ^2υ = -13.8 ° +/- 0.25 ° (ϋΜ8Ο, 589 psi, 20 ° C).

Example 2: (+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -№- {4 - [(8-methylsulfonimidoyl) methyl] pyridin2-yl} pyridin-2-amine.

¹ H NMR (300 MS, BMZO-Y6, 300K): δ [ppm] = 9.80 (δ, 1Η), 8.20 (t, 1Η), 8.16 (t, 1Η), 7.78 (t, 1Η),

7.59 (δ, 1Η), 7.34 (t, 1Η), 7.09 (t, 1Η), 6.90 (t, 2Η), 4.37 (ά, 1Η), 4.33 (ά, 1Η), 3.79 (δ, 3Η), 3.72 (δ, 1Η), 2.87 (δ, 3Η).

Example 3: (-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -№- {4 - [(8-methylsulfonimidoyl) methyl] pyridin2-yl} pyridin-2-amine.

¹ Η NMR (300 MS, VM8O-O ₆ , 300K): δ [ppm] = 9.80 (δ, 1Η), 8.20 (t, 1Η), 8.16 (t, 1Η), 7.78 (t, 1Η),

7.59 (δ, 1Η), 7.34 (t, 1Η), 7.09 (t, 1Η), 6.90 (t, 2Η), 4.37 (ά, 1Η), 4.33 (ά, 1Η), 3.79 (δ, 3Η), 3.72 (δ, 1Η), 2.87 (δ, 3Η).

Example 4: (gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -№- {6-methyl-4 - [(8-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2- amine

Preparation of Intermediate 4.1: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine

A solution of lithium bis- (trimethylsilyl) amide in THP (1M; 20.5 ml; 20.53 mmol; Alp. ) pyridine (2.50 g; 9.78 mmol; L-60 027226

1 gteb1a1e 1.1), tris- (dibenzylideneacetone) dipalladium (0) (0.18 g; 0.20 mmol; A1blsI CHet1ca1 Sotrap Sh.) And 2- (dicyclohexylphosphino) -2 ', 4', 6-triisopropylbiphenyl (0.19 g; 0.39 mmol; A1blsy CHet1ca1 Sotrap Sh.) in ΤΗΡ (16.3 ml) in an argon atmosphere at room temperature. The mixture was stirred at 60 ° C. for 6 hours. The mixture was cooled to 40 ° C. and water (10 ml) was added. The mixture was slowly warmed to room temperature with stirring, solid sodium chloride was added, and the mixture was extracted twice (2x) with ethyl acetate. The mixed organic layers were filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 60%) to obtain the desired product (2.04 g; 8.64 mmol).

¹ H NMR (400 MP /, COC1 ₃ , 300K) δ = 7.95 (t, 1H), 7.20 (t, 1Η), 6.72 (t, 2H), 6.46 (t, 1Η), 4.33 (bt, 2Η), 3.61 (q, 3Η).

Preparation of Intermediate 4.2: (2-chloro-6-methylpyridin-4-yl) methanol

To a stirred solution of 2-chloro-6-methylpyridin-4-carboxylic acid (10.00 g; 55.4 mmol; Maubpbde) in ΤΗΡ (100 ml) at 0 ° С was added a 1M solution of the borane-tetrahydrofuran complex in ΤΗΡ (221, 5 ml; 221.5 mmol). The mixture was allowed to react at room temperature overnight. Then, MeOH (22 ml) was carefully added to the stirred mixture while cooling in an ice bath. The sample was diluted with ethyl acetate and washed with an aqueous solution of sodium hydroxide (1Ν) and a saturated aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. To obtain a pure product (7.24 g; 45.9 mmol), the residue was purified by silica gel column chromatography (OCM / 95: 5).

¹ H NMR (400 MP /, СОС1 ₃ , 300К) δ = 7.18 (q, 1Η), 7.09 (q, 1Η), 4.72 (b, 2Η), 2.55 (q, 3Η), 2.17 (1g, 1Η).

Preparation of Intermediate 4.3: 2-chloro-6-methyl-4 - [(methylsulfanyl) methyl] pyridine

To a stirred solution of (2-chloro-6-methylpyridin-4-yl) methanol (7.20 g; 45.7 mmol) in OMP (200 ml) at 0 ° C was added dropwise thionyl chloride (8.3 ml; 114, 2 mmol). The mixture was allowed to react at 10 ° C. for 2 hours. Then the mixture was concentrated to give the crude product, 2-chloro-4 (chloromethyl) -6-methylpyridine (17.08 g).

The crude 2-chloro-4- (chloromethyl) -6-methylpyridine (8.04 g) was dissolved in acetone (250 ml) and an aqueous solution of sodium methanethiolate (21%, 18.3 ml, 54.8 mmol) was added dropwise with stirring. ; A1bpsy SNet1sa1 Sotrap Shs.). The mixture was stirred at room temperature for 3 hours, then an additional amount of an aqueous solution of sodium methanethiolate (21%, 15.3 ml, 45.7 mmol; L1bpsN CHet1ca1 Sotrap Sh.) Was added and the mixture was stirred at room temperature overnight. In conclusion, an additional amount of an aqueous solution of sodium methanethiolate (21%, 15.3 ml, 45.7 mmol; A1bls.CHet1ca1 Sotrapu Sch.) was added and the mixture was stirred at room temperature for 6 hours. The sample was diluted with ethyl acetate and an aqueous solution of sodium chloride. The mixture was extracted twice with ethyl acetate. The mixed organic layers were filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 20%) to obtain the desired product (7.05 g; 37.6 mmol).

¹ H NMR (400 MP /, СОС1 ₃ , 300К) δ = 7.12 (k, 1Η), 7.05 (k, 1Η), 3.58 (k, 2Η), 2.54 (k, 3Η), 2.03 (k, 3Η).

Preparation of Intermediate 4.4: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {6-methyl-4 [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine

Sample containing 5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine (852 mg; 3.61 mmol), 2chloro-6-methyl-4 - [(methylsulfanyl) methyl] pyridine (677 mg; 3.61 mmol) and cesium carbonate (1410 mg; 4.33 mmol) in dioxane (8.3 ml) were degassed using argon. Under argon atmosphere, (9.9dimethyl-9H-xanthene-4,5-diyl) bis- (diphenylphosphane) (81 mg; 0.14 mmol) and tris (dibenzylideneacetone) dipalladium (0) (69 mg; 0.08) were added. mmol) and the sample was stirred in a closed high-pressure pipe for 3 hours at 100 ° C. In an argon atmosphere, an additional amount of (9.9dimethyl-9H-xanthene-4,5-diyl) -bis- (diphenylphosphane) (81 mg; 0.14 mmol) and tris-61 027226 (dibenzylideneacetone) dipalladium (0) (69) were added mg; 0.08 mmol) and the sample was stirred in a closed high pressure pipe for 20 hours at 100 ° C.

After cooling, the mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 50%) to obtain the desired product (628 mg; 1.62 mmol).

Preparation of intermediates 4.5 and 4.6: (gae) -2,2,2-trifluoro-L - {[(2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} - 6-methylpyridin-4-yl) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide and (gae) -Y - {[(3-bromo-6 - {[5-fluoro-4- (4-fluoro-2 -methoxyphenyl) pyridin-2-yl] amino} -2-methylpyridin-4yl) methyl] (methyl) -X ⁴ -sulfanylidene} -2,2,2-trifluoroacetamide

Under argon, a solution of 2,2,2-trifluoroacetamide (125 mg; 1.11 mmol) in THP (1.0 ml) was added dropwise to a solution of sodium tert-butoxide (71 mg; 0.74 mmol) in THR (1 , 0 ml), so that the temperature of the mixture does not exceed 10 ° C. Then, a fresh solution of 1,3-dibromo-5,5-dimethylhydantoin (158 mg; 0.55 mmol) in THP (1.0 ml) was added dropwise to the stirred mixture, so that the temperature of the mixture did not exceed 10 ° C. Then the mixture was stirred for 10 min at 10 ° C. Finally, a solution of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-methyl-4 - [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2 was added dropwise to the stirred mixture. -amine (286 mg; 0.74 mmol) in THP (1.5 ml), so that the temperature of the mixture does not exceed 10 ° C. The mixture was stirred for 60 min at 10 ° C. The sample was diluted with toluene (4.0 ml) under cooling and an aqueous solution of sodium sulfite (93 mg; 0.74 mmol in 7.0 ml of water) was added so that the temperature of the mixture did not exceed 15 ° C. The sample was extracted three times with ethyl acetate. The mixed organic layers were washed with an aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 100%) to obtain the desired product, 2,2,2 trifluoro-L - {[(2 - {[5-fluoro-4- (4-fluoro-2 methoxyphenyl) pyridin-2-yl] amino} -6-methylpyridin-4-yl) methyl] (methyl) -X ⁴ -sulfaniliden} acetamide (134 mg; 0.27 mmol) and the by-product N - {[(3-brom6 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -2-methylpyridin-4-yl) methyl] (methyl) -X ⁴ sulfanylidene} -2.2, 2-trifluoroacetamide (110 mg; 0.19 mmol).

Intermediate 4.5:

¹ H NMR (400 ΜΗζ, ΟΌΟί ₃ , 300K) δ = 8.18 (t, 1H), 7.70 (s, 1H), 7.33 (bg, 1H), 7.29 (t, 1H), 7.24 (t, 1H), 6.79 (t, 2H), 6.68 (s, 1H), 4.49 (b, 1H), 4.16 (b, 1H), 3.86 (s, 3H), 2.70 (s, 3H), 2.48 (s, 3H).

Intermediate 4.6:

¹ H NMR (400 ΜΗζ, ΟΌΟί ₃ , 300K) δ = 8.18 (s, 1H), 7.84 (s, 1H), 7.33 (s, 1H), 7.29 (t, 1H), 7.23 (t, 1H), 6.78 (t, 2H), 4.77 (b, 1H), 4.36 (b, 1H), 3.86 (s, 3n), 2.80 (s, 3n), 2.63 (s, 3H).

Getting the final product.

To a stirred solution of 2,2,2-trifluoro-L - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} -6-methylpyridin-4-yl) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide (126 mg; 0.25 mmol) in methanol (5.0 ml) and water (1.8 ml) was added dropwise an aqueous solution of potassium hydroxide (25%) to to adjust the pH to 10.5. Ohope® (132 mg; 0.22 mmol) was added and the mixture was stirred at room temperature for 4.5 hours. During this time, the pH was adjusted to a range of 10-11, if necessary, by adding dropwise an aqueous solution of potassium hydroxide ( 25%). After 4.5, Ohope® (33 mg; 0.05 mmol) was additionally added and the mixture was stirred at room temperature for another 2.5 hours. The pH was adjusted to a range of 10-11, if necessary, by adding dropwise an aqueous solution of hydroxide potassium (25%). The mixture was filtered, and the filter cake was washed with a large amount of dichloromethane. The filtrate was washed with an aqueous solution of sodium chloride and then with an aqueous solution of sodium thiosulfate (10%). The organic layer was filtered using a Whatman filter and concentrated. To obtain the desired product (38 mg; 0.09 mmol), the residue was purified by chromatography (from ΌΟΜ to ESM / ethanol 10%).

¹ H NMR (400 ΜΗζ, СОС1 ₃ , 300К) δ = 8.16 (s, 1H), 7.60 (s, 1H), 7.39 (t, 1H), 7.30 (t, 2H), 6.79 (t, 3H), 4.34 (b, 1H), 4.22 (b, 1H), 3.86 (s, 3H), 3.02 (s, 3H), 2.79 (bg, 1H), 2.48 (s, 3H).

Alternative cooking procedure in example 4.

Preparation of Intermediate 4.1: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine

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2-Chloro-5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridine (20.00 g; 78.23 mmol), tris (dibenzylideneacetone) dipalladium (O) (1.433 g; 1.563 mmol) and 2- (dicyclohexylphosphino) -2 ', 4', 6'triisopropylbiphenyl (1.492 g; 3.129 mmol) in anhydrous ΤΗΡ (200 mg) was degassed three times using argon. After 10 min stirring at room temperature, a solution of lithium bis (trimethylsilyl) amide (156.5 ml; 1.0 M; ΤΗΡ) was added and the reaction mixture was degassed an additional three times using argon. The reaction mixture was stirred at a temperature of 60 ° C for 2.5 hours

The reaction mixture was cooled to -20 ° C. An aqueous solution of hydrochloric acid (1.0 M) was added, so that the pH was adjusted to approximately 5. The reaction mixture was left to reach room temperature and stirred for 10 minutes at this temperature. Then the pH was adjusted to 10-11 using an aqueous solution of sodium hydroxide. The reaction mixture was diluted with ethyl acetate and washed twice with a semi-saturated solution of sodium chloride. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified using silica gel column chromatography (gradient: from hexane to ethyl acetate 100%, with 5% dichloromethane in the first 4 volumes of the column, and then with 10% dichloromethane) to obtain the target product (12.04 g; 50.97 mmol) .

¹ H NMR (300 ΜΗζ, ΏΜ8Θ-ά ₆ , 300K): δ [ppm] = 7.85 (b, 1Η), 7.25 (1d, 1Η), 7.08-7.00 (t, 1Η), 6.91-6.81 (t, 1Η ), 6.35 (b, 1Η), 5.84 (δ, 2Η).

Preparation of Intermediate 4.3: 2-chloro-6-methyl-4 - [(methylsulfanyl) methyl] pyridine

To a stirred solution of 4- (bromomethyl) -2-chloro-6-methylpyridine hydrochloride (4.60 g; 17.90 mmol; A1b1aB SjetuAn, bC; for information on the free base see SL8 1227588-90-0) in acetone ( 100 ml) was added dropwise an aqueous solution of sodium methanethiolate (21%, 13.15 ml, 39.38 mmol) while cooling in a water bath at room temperature. The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added and the layers were separated. The organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was purified using silica gel column chromatography (gradient: hexane to hexane / ЕУАс 8: 2) to obtain the desired product (2.60 g; 13.85 mmol).

¹ H NMR (300 ΜΗζ, ΏΜ8Θ-6 ₆ , 300K): δ [ppm] = 7.24 (δ, 1Η), 7.20 (δ, 1Η), 3.66 (δ, 2Η), 2.42 (δ, 3Η), 1.95 ( δ, 3Η).

Preparation of Intermediate 4.4: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-methyl-4 [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine

Sample containing 5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine (692.2 mg; 2.93 mmol), 2chloro-6-methyl-4 - [(methylsulfanyl) methyl] pyridine (500 mg; 2.66 mmol) and cesium carbonate (1302 mg; 4.00 mmol) in dioxane (15 ml) were degassed using argon. Under argon atmosphere, (9.9dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane) (67.8 mg; 0.117 mmol) and tris (dibenzylideneacetone) dipalladium (0) (36.6 mg; 0) were added. , 04 mmol) and the sample was stirred in a closed high pressure pipe for 10 h at 100 ° C.

Five of these samples were combined and diluted with ESAc. The organic layer was washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified using silica gel column chromatography (gradient: from hexane to hexane / ЕУАс 1: 1), which allowed to obtain the desired product (3.75 g; 9.68 mmol).

¹ H NMR (300 ΜΗζ, SPS1 ₃ , 300K): δ [ppm] = 8.16 (b, 1Η), 7.56 (b, 1Η), 7.36-7.29 (t, 2Η), 7.21 (δ, 1Η), 6.85- 6.73 (t, 2Η), 6.72 (δ, 1Η), 3.86 (δ, 3Η), 3.61 (δ, 2Η), 2.45 (δ, 3Η), 2.06 (δ, 3Η).

Preparation of Intermediate 4.5: (gas) -2,2,2-trifluoro - ^ {[(2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} -6-methylpyridine -4-yl) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide

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Preparation of Intermediate 4.6: (gas) -Y - {[(3-bromo-6 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} -2-methylpyridin-4- yl) methyl] (methyl) -X ⁴ -sulfanylidene} -2,2,2 trifluoroacetamide

Under argon, a solution of 2,2,2-trifluoroacetamide (450.7 mg; 3.99 mmol) in THP (2.0 ml) was added dropwise to sodium tert-butoxide (255.5 mg; 2.60 mmol) in anhydrous THP (3.0 ml), so that the temperature of the mixture does not exceed 10 ° C. Then a fresh solution of 1,3-dibromo-5,5-dimethylhydantoin (456.1 mg;

1.60 mmol) in anhydrous THP (3.0 ml) was added dropwise to the stirred mixture, so that the temperature of the mixture did not exceed 10 ° C. Then the mixture was stirred for 10 min at 10 ° C. Finally, a solution of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-methyl-4 [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2- was added dropwise to the stirred mixture. amine (1030 mg; 2.66 mmol) in anhydrous THP (3.0 ml), so that the temperature of the mixture does not exceed 10 ° C. The mixture was stirred for 1 h at 10 ° C. The sample was diluted with toluene (8.0 ml) while cooling and an aqueous solution of sodium sulfite (335 mg; 2.66 mmol in 15.0 ml of water) was added while cooling so that the temperature of the mixture did not exceed 15 ° C. After 10 minutes, the sample was extracted three times with ethyl acetate. The mixed organic phases were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified using silica gel column chromatography (gradient: hexane to ethyl acetate 100%) to obtain the desired product, 2,2,2-trifluoro-L - {[(2 - {[5-fluoro-4- (4-fluoro) -2 methoxyphenyl) pyridin-2-yl] amino} -6-methylpyridin-4-yl) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide (1202 mg; 2.41 mmol; containing 5.5-dimethyl hydantoin) and byproduct X - {[(3-bromo-6 - {[5fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -2-methylpyridin-4-yl) methyl] (methyl) -X ⁴ sulfanilidene} -2,2,2-trifluoroacetamide (7 mg; 0.012 mmol). To remove 5,5-dimethylhydantoin, 3.76 g of the product from 4 lots was purified using silica gel column chromatography (gradient: dichloromethane to dichloromethane / ethanol 95: 5) to obtain the target product (3.39 mg; 6.80 mmol) .

Intermediate 4.5:

¹ H NMR (300 M1K ΌΜ 8Θ-ά ₆ , 300 K): δ [ppm] = 9.85 (s, 1H), 8.17 (ά, 1H), 7.65-7.57 (t, 2H), 7.34 (άά, 1H), 7.09 (άά, 1H), 6.96-6.87 (t, 1H), 6.66 (s, 1H), 4.56-4.48 (t, 1H), 4.42-4.33 (t, 1H), 3.80 (s, 3H), 2.77 (s , 3H); 2.34 (s, 3H).

Intermediate 4.6:

( ¹ H-NMR was taken from another series): ¹ H NMR (300 M1K OM8O0, 300K): δ [ppm] = 10.02 (s, 1H), 8.18 (ά, 1H), 7.83 (s, 1H), 7.52 ( ά, 1H), 7.38-7.31 (t, 1H), 7.13-7.06 (t, 1H), 6.96-6.87 (s, 1H), 4.67-4.55 (t, 2H), 3.80 (s, 3H), 2.92 ( s, 3H), 2.51 (bg.s., 3H).

Preparation of intermediates 4.7 and 4.8:

3.76 g of racemic 2,2,2-trifluoro-L - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} -6-methylpyridin-4- il) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide was separated by chiral preparative HPLC:

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System: Αβίΐεηί: Rger 1200, 2xRger Richard, OBA, M \ ¥ b, Rger RS Speaker: Syga1rak ΙΑ 5 μm 250x30 mm, No. 010 Solvent b: hexane / ethanol / diethylamine 50: 50: 0.1 (ν / ν / ν) Flow rate: 45 ml / min. Temperature: Room temperature Solution: 3760 / 30.4 b OSM / MeOH Volume entered samples: 38 x 0.8 w Detection: UV, 280 nm Fractions retention time (in minutes) purity (%) exit Specific optical rotation: Intermediate substance 4.7 5.3 - 6.8 minutes 95.5%; her: 100% 1520 mg (3.05 mmol) [α] _ο ^2υ = + 113.4 ° (1.00, ϋΜδΟ) Intermediate substance 4.8 7.2 - 10.5 minutes 97.1%; her: 98.7% 1480 mg (2.97 mmol) [α] _ο ²⁰ = -112.1 ° (1.00, ϋΜδΟ)

Intermediate 4.7: (+) - 2,2,2-trifluoro-L - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6 -methylpyridin-4-yl) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide

¹ H NMR (400 MH /, VM8O-d ₆ , 300 K): δ [ppm] = 9.83 (δ, 1H), 8.17 (ά, 1H), 7.63-7.59 (t, 2H), 7.34 (άά, 1H) 7.09 (άά, 1H), 6.94-6.88 (t, 1H), 6.66 (δ, 1H), 4.52 (ά, 1H), 4.37 (ά, 1H), 3.80 (δ, 3H), 2.77 (δ, 3H) ), 2.34 (δ, 3H).

Intermediate 4.8: (-) - 2,2,2-trifluoro-L - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6 -methylpyridin-4-yl) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide

¹ H NMR (400 MH /, ^ M8O-300 ₆ , 300K): δ [ppm] = 9.83 (δ, 1H), 8.17 (ά, 1H), 7.63-7.59 (t, 2H), 7.34 (άά, 1H ), 7.09 (άά, 1H), 6.94-6.88 (t, 1H), 6.66 (δ, 1H), 4.52 (ά, 1Н), 4.37 (ά, 1Н), 3.80 (δ, 3Н), 2.77 (δ, 3H), 2.34 (δ, 3H).

Alternative preparation of the final product (Example 4): (gas) -5-fluoro-4- (4-fluoro-2methoxyphenyl) -Y- {6-methyl-4 - [(8-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine

(rac) -2,2,2-trifluoro-L - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6methylpyridin-4-yl ) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide (150 mg; 0.301 mmol) was dissolved in methanol (18.0 ml) and water (9.0 ml). At 0-5 ° C, the pH was adjusted to 9-10 using an aqueous solution of potassium hydroxide (15%). At this temperature, Ohope® (157.0 mg; 0.256 mmol) was added in several parts and the pH was adjusted in the range of 9-10. The mixture was stirred for 1 h at 05 ° C, and the pH was adjusted to 9-10.

The pH in the mixture was adjusted to a pH of 6-7 using 2.0 M hydrochloric acid. A saturated aqueous solution of sodium chloride was added, and the reaction mixture was extracted three times with dichloromethane. The mixed organic phases were washed with an aqueous solution of thiosulfate (10%), dried over magnesium sulfate and concentrated. The residue was purified using silica gel column chromatography (gradient: dichloromethane to dichloromethane / ethanol 9: 1) to obtain the desired product (100 mg; 0.239 mmol).

¹ H NMR (300 ΜΗζ, VM8O minutes _6, 300K): δ [ppm] = 9.76 (s, 1Η), 8.18 (d, 1Η), 7.67 (d, 1Η), 7.57 (s, 1Η), 7.38- 7.30 (t, 1Η), 7.13-7.06 (t, 1Η), 6.96-6.87 (t, 1Η), 6.77 (s, 1Η), 4.37-4.25 (t, 2Η), 3.80 (s, 3Η), 3.71 ( h, 1Η), 2.87 (s, 3Η), 2.35 (s, 3Η).

Example 5: (gas) -5-bromo-K- [5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] -6-methyl-4 - [(8methylsulfonimidoyl) methyl] pyridin- 2-amine

To a stirred solution of K - {[(3-bromo-6 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} -2-methylpyridin-4-yl) methyl] (methyl ) -X ⁴ -sulfanylidene} -2,2,2-trifluoroacetamide (161 mg; 0.28 mmol, intermediate 4.6) in methanol (15.0 ml) and water (5.0 ml) was added dropwise an aqueous solution of hydroxide potassium (25%) in order to adjust the pH to 10.5. Ohope® (146 mg; 0.24 mmol) was added and the mixture was stirred at room temperature for 4 hours. During this time, the pH was adjusted to a range of 10-11, if necessary, by adding dropwise an aqueous solution of potassium hydroxide (25% ) After 4, an additional portion of Ohope® (50 mg; 0.08 mmol) was added and the mixture was stirred at room temperature for another 2.5 hours. The pH was adjusted to a range of 10-11, if necessary, by adding dropwise an aqueous solution of potassium hydroxide (25%). The mixture was filtered, and the filter cake was washed with a large amount of BSM / MeOH (2: 1). The pH of the filtrate was adjusted to 6.5 using an aqueous solution of hydrogen chloride (15%), then it was diluted with OSM and washed with an aqueous solution of sodium chloride. Finally, the organic layer was washed with an aqueous solution of sodium thiosulfate (10%). The organic phase was filtered using a Whatman filter and concentrated. To obtain the desired product (44 mg; 0.09 mmol), the residue was purified by chromatography (from OSM to BSM / ethanol 5%).

¹ H NMR (400 M1K SBS13, 300K) δ = 8.14 (t, 1Η), 7.80 (s, 1Η), 7.32 (t, 2H), 7.29 (t, 1Η), 6.78 (t, 2H), 4.87 (th , 1Η), 4.59 (s, 1H), 3.85 (s, 3Η), 3.07 (s, 3Η), 2.99 (bg, 1Η), 2.62 (s, 3Η).

Example 6: (gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -K- {6-methoxy-4 - [(8-methylsulfonimidoyl) -

Preparation of Intermediate 6.1: 2-chloro-6-methoxy-4 - [(methylsulfanyl) methyl] pyridine

An aqueous solution of sodium methanethiolate (21%, 1.4 ml) was added dropwise to a stirred solution of 4- (bromomethyl) -2-chloro-6-methoxypyridine (1000 g; 4.2 mmol, 2HEPEX Mo1CI1AGHITYE) in acetone (50 ml). , 4.2 mmol; L1ypsy Syet1sa1 Sotrapu Ys.) When cooled in a water bath at room temperature. The mixture was stirred at room temperature for 3 hours. The sample was diluted with ethyl acetate and an aqueous solution of sodium chloride. The mixture was extracted twice (2x) using ethyl acetate. The mixed organic layers were filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 10%) to obtain the desired product (738 mg; 3.6 mmol).

¹ H NMR (400 ΥΗζ, CBC1 ₃ , 300K) δ = 6.92 (s, 1Η), 6.61 (s, 1Η), 3.96 (s, 3Η), 3.56 (s, 2H), 2.03 (s, 3Η).

Preparation of Intermediate 6.2: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -K- {6-methoxy-4 [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine

- 66 027226

A mixture of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine (1281 mg; 5.4 mmol, intermediate 4.1), 2-chloro-6-methoxy-4 - [(methylsulfanyl) methyl ] pyridine (724 mg; 3.6 mmol), chlorine (2-dicyclohexylfoeophino-2 ', 4', 6'-triisopropyl-1, G-biphenyl) [2- (2-aminoethyl) phenyl] palladium (P) methyl tert-butyl ether adduct (294 mg; 0.36 mmol; ABSC OTN & CO. KO) and 2 (dicyclohekeylphoefino) -2 ', 4', 6'-triisopropylbiphenyl (170 mg; 0.36 mmol; A1bpsB S.Betuia 1 Sotrapu Is.) and phosphate potassium (3773 mg; 17.77 mmol) in toluene (84 ml) and \ M1P (10 ml) were stirred under argon at 130 ° C in a closed vessel for 4 hours. After cooling The sample was diluted with an ESM and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 35%) to obtain a pure product (1212 mg; 3.00 mmol).

¹ H NMR (400 MH /, SPS1 ₃ , 300K) δ = 8.15 (t, 1H), 7.91 (t, 1H), 7.29 (t, 1H), 7.21 (s, 1H), 6.77 (t, 3H), 6.28 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.58 (s, 2H), 2.06 (s, 3H).

Preparation of Intermediate 6.3: (^ ac) -2,2,2-trifluoro-N - {[(2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} -6 -methoxypyridin-4-yl) methyl] (methyl) -X ⁴ eulphanylidene} acetamide

Under argon, a solution of 2,2,2-trifluoroacetamide (252 mg; 2.23 mmol) in TNB (2.0 ml) was added dropwise to a solution of sodium tert-butoxide (143 mg; 1.49 mmol) in TNB (2 , 0 ml), so that the temperature of the mixture does not exceed 10 ° C. Then, a fresh solution of 1,3-dibromo-5,5-dimethylhydantoin (255 mg; 0.89 mmol) in TNB (2.0 ml) was added dropwise to the stirred mixture, so that the temperature of the mixture did not exceed 10 ° C. Then the mixture was stirred for 10 min at 10 ° C. Finally, a solution of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {6-methoxy-4 [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2- was added dropwise to the stirred mixture. amine (600 mg; 1.49 mmol) in TNB (3.0 ml), so that the temperature of the mixture does not exceed 10 ° C. The mixture was stirred for 3.5 hours at 10 ° C. The sample was diluted with toluene (8.0 ml) under cooling and an aqueous solution of sodium sulfite (187 mg; 1.49 mmol in 14.0 ml of water) was added so that the temperature of the mixture did not exceed 15 ° C. The sample was extracted three times with ethyl acetate. The mixed organic layers were washed with an aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. To obtain the target product (37 mg; 0.07 mmol), the residue was purified using silica gel column chromatography (from ESM to □ SM gganol 5%).

¹ H NMR (400 MH /, SPS1 ₃ , 300K) δ = 8.18 (t, 1H), 7.56 (t, 1H), 7.29 (t, 2H), 7.12 (t, 1H), 6.78 (t, 2H), 6.25 (s, 1H), 4.52 (b, 1H), 4.07 (b, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.70 (s, 3H).

Getting the final product.

To a stirred solution of 2,2,2-trifluoro-N - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} -6-methylpyridin-4-yl) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide (32 mg; 0.06 mmol) in methanol (1.0 ml) and water (0.6 ml) was added dropwise an aqueous solution of potassium hydroxide (25%) to to adjust the pH to 10.5. Ohope® (32 mg; 0.05 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. During this time, the pH was adjusted to a range of 10-11, if necessary, by adding dropwise an aqueous solution of potassium hydroxide ( 25%). The mixture was filtered, and the filter cake was washed with a large amount of dichloromethane. The filtrate was washed with an aqueous solution of sodium chloride and then with an aqueous solution of sodium thiosulfate (10%). The organic layer was filtered using a Whatman filter and concentrated. To obtain the desired product (9 mg; 0.02 mmol), the residue was purified using preparative HPLC.

- 67 027226

System: \ Wa1sg8 Ai1oripsa1yup8u81esh: Rishr 2545, 8atr1s Mapadeg 2767, CEO, ϋΑϋ 2996, EZO 2424, 3 (D) 3001 Speaker: ХВп§с1с С18 5 μm 100x30 mm Solvent: A = H ₂ O + 0.1% HCOOH B = ms Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow rate: 50 ml / min. Temperature: Room temperature Solution: Mach 250 mg / check 2.5 bw ϋΜ3Ο og ϋΜΕ Volume entered samples: 1 x 2.5 w Detection: DMD, scanning range 210-400 nm M3 Ε8Ι +, Ε8Ι-, scanning range 160-1000 t / ζ

¹ H NMR (400 MH, CBC1 ₃ , 300K) δ = 8.16 (t, 1H), 7.78 (t, 1H), 7.26 (t, 2H), 7.00 (t, 1H), 6.77 (t, 2H), 6.36 (t, 1H), 4.30 (1, 1H), 4.19 (1, 1H), 3.88 (δ, 3H), 3.85 (δ, 3H), 3.01 (δ, 3H), 2.79 (bh, 1H).

Alternative cooking procedure in example 6: (gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) K- {6-methoxy-4 - [(3-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridine -2-amine

To a solution of (rac) -ethyl - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6 methoxypyridin-4-yl) methyl] (methyl) oxo-X ⁶ -sulfanylidene} carbamate (290 mg; 0.57 mmol; example 15) in ethanol (6.3 ml) under argon atmosphere was added a fresh 1.5 M solution of sodium ethanolate in ethanol (1.5 ml; 2, 25 mmol). The sample was stirred at 60 ° C for 4 hours. After cooling, the sample was diluted with an aqueous solution of sodium chloride and extracted three times with ethyl acetate. The mixed organic layers were filtered using a Whatman filter and concentrated to give the desired product (257 mg; 0.0.59 mmol).

¹ H NMR (400 MH, CBC1 ₃ , 300K) δ = 8.16 (t, 1H), 7.78 (t, 1H), 7.26 (t, 2H), 7.00 (t, 1H), 6.77 (t, 2H), 6.36 (t, 1H), 4.30 (1, 1H), 4.19 (1, 1H), 3.88 (δ, 3H), 3.85 (δ, 3H), 3.01 (δ, 3H), 2.79 (bh, 1H).

Example 7: (gas) -K- {6-chloro-4 - [(3-methylsulfonimidoyl) methyl] pyridin-2-yl} -5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-amine

Preparation of Pyridine Intermediate 7.1: 2-chloro-6-methoxy-4 - [(methylsulfanyl) methyl] -

Mixture of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine (2000 mg; 8.47 mmol, intermediate 4.1), (2,6-dichloropyridin-4-yl) methanol (1507 mg ; 8.47 mmol; ABSC STH & CO. KS), chlorine (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1, G-biphenyl) [2- (2-aminoethyl) phenyl] palladium (P ) methyl tert-butyl ether adduct (700 mg; 0.85 mmol; ABSC STH & CO. KS) and 2 (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl (404 mg; 0.85 mmol; AMPS Syet1ca1 Sotrapa x.) And potassium phosphate (8986 mg; 42.33 mmol) in toluene (40 ml) and NMR (4 ml) were stirred under argon at 110 ° C for 135 minutes. After cooling, the sample was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (from hexane 68 027226 to hexane / ethyl acetate 50%) to obtain a pure product (1350 mg; 3.57 mmol).

¹ H NMR (400 ΜΗζ, ά ₆ -ΌΜ8Ο, 300K) δ = 10.06 (s, 1H), 8.25 (t, 1H), 7.71 (t, 1H), 7.56 (t, 1H), 7.35 (t, 1H) 7.10 (t, 1H), 6.93 (t, 1H), 6.85 (t, 1H), 5.47 (1g, 1H), 4.49 (ά, 2H), 3.81 (s, 3H).

Preparation of Intermediate 7.2: ^ [6-chloro-4 - [(methylsulfanyl) methyl] pyridin-2yl} -5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine

To a stirred solution of (2-chloro-6 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methanol (1.47 g; 3.89 mmol ) thionyl chloride (0.71 ml; 9.73 mmol) was added dropwise in EMR (43 ml) at 0 ° C. The mixture was allowed to react at room temperature for 2 hours. The mixture was then concentrated to obtain crude ^ [6-chloro-4- (chloromethyl) pyridin-2-yl] -5 fluoro-4- (4-fluoro-2-methoxyphenyl) pyridine -2-amine (2.85 g).

The crude ^ [6-chloro-4- (chloromethyl) pyridin-2-yl] -5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin2-amine (2.85 g) was dissolved in acetone (87 ml) and with stirring, an aqueous solution of sodium methanethiolate was added dropwise (21%, 5.2 ml, 15.58 mmol; Apsy Syet1ca1 Sotrapu Ys.). The mixture was stirred at room temperature for 6 hours. The mixture was diluted with an aqueous solution of sodium chloride and extracted twice with ethyl acetate. The mixed organic layers were filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 20%) to obtain the desired product (1.24 g; 3.04 mmol).

¹ H NMR (400 ΥΙΙΙζ. SPS1 ₃ , 300K) δ = 8.17 (s, 1H), 7.50 (t, 3H), 7.32 (t, 1H), 6.90 (s, 1H), 6.79 (t, 2H), 3.87 (s, 3H), 3.62 (s, 2H), 2.07 (s, 3H).

Preparation of Intermediate 7.3: (gas) - \ - {| (2-chloro-6 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} pyridin-4-yl) methyl ] (methyl) -X ⁴ -sulfanylidene} -2,2,2 trifluoroacetamide

Under argon, a solution of 2,2,2-trifluoroacetamide (312 mg; 2.76 mmol) in THP (2.0 ml) was added dropwise to a solution of sodium tert-butoxide (176 mg; 1.84 mmol) in THR (2 , 0 ml), so that the temperature of the mixture does not exceed 10 ° C. Then, a fresh solution of 1,3-dibromo-5,5-dimethylhydantoin (394 mg; 1.38 mmol) in THP (3.0 ml) was added dropwise to the stirred mixture so that the temperature of the mixture did not exceed 10 ° C. Then the mixture was stirred for 10 min at 10 ° C. Finally, a solution of No. {6-chloro-4 - [(methylsulfanyl) methyl] pyridin-2-yl} -5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-amine (dropwise) was added dropwise to the stirred mixture. 750 mg; 1.84 mmol) in THP (3.0 ml), so that the temperature of the mixture does not exceed 5 ° C. The mixture was stirred for 3 hours at 5 ° C. The sample was diluted with toluene (5.0 ml) under cooling and an aqueous solution of sodium sulfite (232 mg; 1.84 mmol in 5.0 ml of water) was added so that the temperature of the mixture did not exceed 15 ° C. The sample was extracted three times with ethyl acetate. The mixed organic layers were washed with an aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 85%) to obtain the desired product (363 mg; 0.70 mmol).

¹ H NMR (400 ΥΙΙΙζ. SPS1 ₃ , 300K) δ = 8.18 (s, 1H), 8.12 (bg, 1H), 7.84 (s, 1H), 7.37 (t, 1H), 7.31 (t, 1H), 6.80 (t, 3H), 4.46 (ά, 1H), 4.24 (ά, 1H), 3.87 (s, 3H), 2.75 (s, 3H).

Getting the final product.

To a stirred solution of ^ {[(2-chloro-6 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methyl] (methyl) -X ⁴ -sulfanilidene} -2,2,2-trifluoroacetamide (495 mg; 0.95 mmol) in methanol (15.0 ml) and water (6.7 ml) was added dropwise an aqueous solution of potassium hydroxide (25%) so that to adjust the pH to 10.5. O \ op® (498 mg; 0.81 mmol) was added and the mixture was stirred at room temperature for 90 minutes. During this time, the pH was adjusted in the range of 10-11, if necessary, by adding dropwise an aqueous solution of potassium hydroxide (25%). The mixture was filtered and the filter cake washed with a large amount of dichloromethane and methanol. The pH of the filtrate was adjusted to 6-7 using an aqueous solution of hydrogen chloride (15%). The filtrate was washed with an aqueous solution of sodium chloride and then with an aqueous solution.

69,027,226 sodium thiosulfate (10%). The organic phase was filtered using a Whatman filter and concentrated. To obtain the desired product (118 mg; 0.27 mmol), the residue was purified by chromatography (OSM to ESM / ethanol 50%).

Example 8: (gas) -2- {8 - [(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) amino} pyridin-4yl) methyl] sulfonimidoyl} ethanol

Preparation of Intermediate 8.1: 2 - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin2-yl] amino} pyridin-4-yl) methyl] sulfanyl} ethanol

Sample containing 2-chloro-5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridine (1387 mg; 5.43 mmol, intermediate 1.1), 2 - {[(2-aminopyridin-4-yl) methyl] sulfanyl} ethanol (2000 mg; 10.85 mmol; ichrOg§8up! b1313! b.), (9,9-dimethyl-9H-xanthene-4,5-diyl) -bis- (diphenylphosphane) (138 mg; 0.24 mmol) and cesium carbonate (2652 mg; 8.14 mmol) in dioxane (14.2 ml) were degassed using argon. In an argon atmosphere, tris (dibenzylideneacetone) dipalladium (0) (75 mg; 0.08 mmol) was added and the sample was stirred in a closed vessel for 23 h at 100 ° C. After cooling, the sample was diluted with OSM and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. To obtain the desired product (1500 mg; 3.72 mmol), the residue was purified by silica gel column chromatography (from OCM to ESM / JUN 5%) and, finally, it was crystallized from an ESM / diisopropyl ether mixture.

¹ H NMR (400 MN /. СОС1 ₃ , 300К) δ = 8.15 (t, 2H), 7.55 (t, 3H), 7.28 (t, 1H), 6.76 (t, 3H), 3.82 (s, 3H), 3.72 (! G, 2H), 3.68 (s, 2H), 2.66 (! G, 2H).

Preparation of Intermediate 8.2: X- (4 - {[(2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) sulfanyl] methyl} pyridin-2-yl) -5-fluoro-4- (4-fluoro -2-methoxyphenyl) pyridin-2-amine

To a stirred solution of 2 - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methyl] sulfanyl} ethanol (1490 mg; 3, 69 mmol) and imidazole (254 mg; 3.73 mmol) in OSM (16 ml) was added tert-butyldimethylchlorosilane (556 mg; 3.69 mmol) at room temperature. The reaction mixture was stirred for 21 hours, then additional imidazole (51 mg; 0.74 mmol) and tert-butyldimethylchlorosilane (111 mg; 0.74 mmol) were added. The reaction mixture was stirred at room temperature for another 30 hours. The mixture was diluted with water and extracted three times with an ESM. The mixed organic layers were filtered using a Whatman filter and concentrated. To obtain the desired product (1358 mg; 2.62 mmol), the residue was purified by silica gel column chromatography (OCM to ESM / JUN 5%).

¹ H NMR (400 MN /. СОС1 ₃ , 300К) δ = 8.17 (t, 2H), 7.64 (t 1H), 7.39 (t, 2H), 7.31 (t, 1H), 6.86 (t 1H), 6.78 ( t, 2H), 3.85 (s, 3H), 3.79 (! g, 2H), 3.74 (s, 2H), 2.62 (! g, 2H), 0.92 (s, 9H), 0.08 (s, 6H).

Preparation of Intermediate 8.3: (gas) -X - {(2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) [(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin-4-yl) methyl] -λ ⁴ sulfanylidene} -2,2,2-trifluoroacetamide

Under argon, a solution of 2,2,2-trifluoroacetamide (184 mg; 1.63 mmol) in THP (4.0 ml) was added dropwise to a solution of sodium tert-butoxide (104 mg; 1.09 mmol) in THR (5 , 0 ml), so that the temperature of the mixture does not exceed 10 ° C. Then, a fresh solution of 1,3-dibromo-5,5-dimethylhydantoin (186 mg; 0.65 mmol) in THP (4.0 ml) was added dropwise to the stirred mixture so that the temperature of the mixture did not exceed 10 ° C. Then the mixture was stirred for 10 min at 10 ° C. Finally, to mix

- 70 027226 was added dropwise a solution of No. (4 - {[(2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) sulfanyl] methyl} pyridin-2-yl) -5-fluoro-4- (4- fluoro-2-methoxyphenyl) pyridin-2-amine (562 mg; 1.09 mmol) in THP (5.0 ml), so that the temperature of the mixture does not exceed 5 ° C. The mixture was stirred for 5 hours at 5 ° C. The sample was diluted with toluene (5.0 ml) under cooling and an aqueous solution of sodium sulfite (137 mg; 1.09 mmol in 4.0 ml of water) was added so that the temperature of the mixture did not exceed 15 ° C. The sample was extracted three times with ethyl acetate. The mixed organic phases were washed with an aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. To obtain the desired product (293 mg; 0.47 mmol), the residue was purified by chromatography (from PCM to ECM / EUN 5%).

¹ H NMR (400 MH, CPC13, 300K) δ = 8.27 (t, 1H), 8.17 (t, 1H), 7.72 (§, 1H), 7.38 (t, 2H), 7.30 (t, 1H), 6.79 (t, 3H), 4.50 (ά, 1H), 4.41 (ά, 1H), 4.09 (t, 2H), 3.85 (§, 3H), 3.18 (t, 2H), 0.92 (§, 9H), 0.13 ( §, 3H), 0.12 (§, 3H).

Getting the final product.

To a stirred solution of ^ {(2 - {[tert-butyl (dimethyl) silyl] oxy} ethyl) [(2 - {[5-fluoro-4- (4-fluoro2-methoxyphenyl) pyridin-2-yl] amino} pyridine -4-yl) methyl] -X ⁴ -sulfanylidene} -2,2,2-trifluoroacetamide (188 mg; 0.30 mmol) in methanol (45.0 ml) and water (10.0 ml) was added dropwise aqueous potassium hydroxide solution (25%) in order to adjust the pH to 10.5. Ohope® (156 mg; 0.25 mmol) was added and the mixture was stirred at room temperature for 17 hours. During this time, the pH was adjusted to a range of 10-11, if necessary, by adding dropwise an aqueous solution of potassium hydroxide (25% ) The mixture was filtered and the filter cake washed with a large amount of dichloromethane and methanol. The pH of the filtrate was adjusted to 6-7 using an aqueous solution of hydrogen chloride (15%). The filtrate was washed with an aqueous solution of sodium chloride and then with an aqueous solution of sodium thiosulfate (10%). The organic layer was filtered using a Whatman filter and concentrated. To obtain the desired product (50 mg; 0.12 mmol), the residue was purified using preparative HPLC.

System: Аа1егз АшорипПсаОOнOnOlet: Riter 2545, 8atr1e Mapadeg 2767, СРО, ϋΑϋ 2996, Е8О 2424, 3 (20 3001 Speaker: ХВп§с1е С18 5 μm 100x30 mm Solvent: A = H ₂ O + 0.1% HCOOH B = MeCI Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow rate: 50 ml / min. Temperature: Room temperature Solution: Mach 250 mg / check 2.5 t ϋΜ3Ο og ϋΜΡ Volume entered samples: 1 x 2.5 tb Detection: DMD, scanning range 210-400 nm M3 Ε8Ι +, Ε8Ι-, scanning range 160-1000 t / ζ

¹ H NMR (400 MN / a, and _6- PM8O, 300K) δ = 9.89 (§, 1H), 8.18 (t, 2H), 7.71 (t, 1H), 7.66 (§, 1H), 7.34 (t, 1H) ), 7.09 (t, 1H), 6.91 (t, 1H), 6.80 (t, 1H), 5.30 (! G, 1H), 4.62 (ά, 1H), 4.45 (ά, 1H), 3.82 (t, 1H) ), 3.80 (S, 3H), 3.74 (t, 1H), 3.36 (t, 1H), 3.18 (t, 1H).

Example 9: (gas) -H- (4 - {[3- (2-aminoethyl) sulfonimidoyl] methyl} pyridin-2-yl) -5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-amine

Preparation of Intermediate 9.1: tert-butyl- (2- {8 - [(2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} pyridium-4-yl) methyl] -H- (trifluoroacetyl) sulfinimidoyl} ethyl) carbamate

To a stirred solution of (2 - {[5-fluoro-4- (4-fluoro-2-methoxypheyl) pyridium-2yl] amio} pyridium-4-yl) methaiol (2000 mg; 5.83 mmol, intermediate 1.3) in PMP (60 ml) at

- 71 027226

Thionyl chloride (1.06 ml; 14.56 mmol) was added dropwise to 0 ° C. The mixture was stirred for 2.5 hours at room temperature. The sample was diluted with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and was extracted five times using an ESM. The mixed organic layers were filtered using a Whatman filter and concentrated to give crude Ν- [4 (chloromethyl) pyridin-2-yl] -5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine (1730 mg ), which was used in the next step without further purification.

The residue was dissolved in EMR (12.5 ml) and with stirring, cesium carbonate (3116 mg; 9.56 mmol) and tert-butyl (2-sulfanylethyl) carbamate (874 mg; 4.78 mmol; Α1ά ^ Ь Сет1с1 Sotrapu Ys were added .). The mixture was stirred for 16 hours at room temperature before it was diluted with an aqueous solution of sodium chloride and extracted twice with ethyl acetate. The mixed organic layers were filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 50%) to obtain the desired product (1260 mg; 2.51 mmol).

¹ H NMR (400 MB SOS1 ₃ , 300K) δ = 8.18 (t, 2H), 7.59 (t, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.31 (t, 1H), 6.84 ( t, 1H), 6.75 (t, 2H), 4.93 (b, 1H), 3.85 (s, 3H), 3.69 (s, 2H), 3.32 (t, 2H), 2.61 (! g, 2H), 1.47 ( s, 9H).

Preparation of Intermediate 9.2: (gas) -tert-butyl (2- {8 - [(2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} pyridin-4-yl ) methyl] -Y- (trifluoroacetyl) sulfinimidoyl} ethyl) carbamate

Under argon, a solution of 2,2,2-trifluoroacetamide (202 mg; 1.79 mmol) in THP (0.6 ml) was added dropwise to a solution of sodium tert-butoxide (115 mg; 1.19 mmol) in THR (1 , 0 ml), so that the temperature of the mixture does not exceed 10 ° C. Then a fresh solution of 1,3-dibromo-5,5-dimethylhydantoin (222 mg; 0.78 mmol) in THP (1.0 ml) was added dropwise to the stirred mixture so that the temperature of the mixture did not exceed 10 ° C. Then the mixture was stirred for 10 min at 10 ° C. Finally, a solution of tert-butyl (2 - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) was added dropwise to the stirred mixture. methyl] sulfanyl} ethyl) carbamate (600 mg; 1.19 mmol) in THP (1.0 ml), so that the temperature of the mixture does not exceed 10 ° C. The mixture was stirred for 80 min at 10 ° C. The sample was diluted with toluene (3.0 ml) under cooling and an aqueous solution of sodium sulfite (150 mg; 1.19 mmol in 4.5 ml of water) was added so that the temperature of the mixture did not exceed 15 ° C. The sample was extracted three times with ethyl acetate. The mixed organic layers were washed with an aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 30% / 70%) to obtain the desired product (579 mg; 0.94 mmol).

¹ H NMR (400 MH, COCO ₃ , 300K) δ = 8.48 (L, 1H), 8.25 (t, 1H), 8.18 (t, 1H), 7.77 (b, 1H), 7.48 (t, 1H), 7.30 (t, 1H), 6.80 (t, 3H), 5.77 (bt, 1H), 4.40 (s, 2H), 3.85 (t, 4H), 3.71 (t, 1H), 3.45 (t, 1H), 3.32 (t, 1H), 1.45 (s, 9H).

Preparation of Intermediate 9.3: (gas) -tert-butyl (2- {8 - [(2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} pyridin-4-yl ) methyl] sulfonimidoyl} ethyl) carbamate

To a stirred solution of tert-butyl (2- {8 - [(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methyl] -Y- (trifluoroacetyl) sulfinimidoyl} ethyl) carbamate (438 mg; 0.71 mmol) in methanol (14.0 ml) and water (5.0 ml) was added dropwise an aqueous solution of potassium hydroxide (25%) in order to adjust the value pH up to 10.5. Ohope® (373 mg; 0.61 mmol) was added and the mixture was stirred at room temperature for 2 hours. During this time, the pH was adjusted to a range of 10-11, if necessary, by adding dropwise an aqueous solution of potassium hydroxide (25% ) The mixture was filtered, and the filter cake was washed with a large amount of dichloromethane. The pH of the filtrate was adjusted to 6-7 using an aqueous solution of hydrogen chloride (15%). The filtrate was washed with an aqueous solution of sodium chloride and then with an aqueous solution of sodium thiosulfate (10%). The organic phase was filtered using a Whatman filter and concentrated. The residue was purified using chromatography (hexane to ethyl acetate) to obtain the desired product (139 mg; 0.26 mmol).

- 72 027226 ¹ Н NMR (400 МН /, СЭС1з, 300К) δ = 8.26 (t, 1Η), 8.17 (q, 1Η), 7.71 (q, 1Η), 7.53 (t, 1Η), 7.30 (t,

2H), 6.92 (t, 1Η), 6.78 (t, 2H), 5.55 (b, 1Η), 4.35 (b, 1Η), 4.22 (b, 1Η), 3.85 (q, 3Η), 3.72 (t, 2H) ), 3.27 (t,

2H), 1.47 (q, 9Η).

Getting the final product.

To a stirred solution of (rac) -tert-butyl (2- {8 - [(2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} pyridin-4-yl) methyl ] sulfonimidoyl} ethyl) carbamate (136 mg; 0.26 mmol) in OSM (10.7 ml) was added trifluoroacetic acid (0.59 ml; 7.65 mmol) and the mixture was stirred overnight at room temperature. The sample was concentrated and, to obtain the desired product (38 mg; 0.09 mmol), the residue was purified by preparative HPLC.

System: \ Wa1egz Ai1oripisa1yup8u81et: Ritr 254, 8atr1e Mapadeg 2767, SRO, ϋΑϋ 2996, 3 (D) 3100 Speaker: HVpdOe C18 5 μm 100x30 mm Solvent: A = H ₂ O + 0.2% vol. ΝΗ ₃ (32%) B = MES Gradient: 0.5 min., Feed (12% B, 25 ml / min.); 0.5 - 5.5 minutes 2550% B Flow rate: 70 ml / min. Temperature: Room temperature Solution: 182 mg / 1.7 ml ϋΜ8Ο Volume entered samples: 4 x 0.425 ml Detection: DMD, scanning range 210-400 nm M3 Ε3Ι +, Ρ8Ι-, scanning range 160-1000 t / ζ retention time (in minutes) purity(%) 4.6-4.9 99

¹ H NMR (400 MN /, СОС1 ₃ , 300К) δ = 8.24 (t, 1Η), 8.13 (t, 1Η), 7.67 (q, 1Η), 7.46 (t, 1Η), 7.38 (q, 1Η), 7.28 (t, 1Η), 6.91 (t, 1Η), 6.75 (t, 2H), 4.40 (b, 1Η), 4.28 (b, 1n), 3.83 (q, 3Η), 3.32 (t, 2H), 3.17 (t, 2H).

Example 10: {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin-4-yl) methyl] (methyl) oxide-X ⁶ -sulfanylidene } cyanamide

To a stirred solution of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4 - [(8-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine (75 mg; 0.19 mmol; example 3; enantiomer 2) and 4dimethylaminopyridine in OSM (1.0 ml) at room temperature cyanogen bromide (39 mg; 0.37 mmol) was added. The mixture was stirred for 24 hours at room temperature before it was concentrated under reduced pressure. To obtain the desired product (36 mg; 0.08 mmol), the residue was purified using preparative HPLC.

- 73 027226

System: AUaSChgv Ai1oripysayop8u81et: Riter 2545, 8atr1e Mapaueg 2767, SRO, ϋΑϋ 2996, E8O 2424, δ (2ϋ 3001 Speaker: ХВп§с1е С18 5 μm 100x30 mm Solvent: A = H ₂ O + 0.1% HCOOH B = ΜεΟΝ Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Flow rate: 50 ml / min. Temperature: Room temperature Solution: Mach 250 mg / check 2.5 bh ϋΜδΟ og ϋΜΡ Volume entered samples: 1 x 2.5 w Detection: DMD, scanning range 210-400 nm M8 Ε8Ι +, Ε8Ι-, scanning range 160-1000 t / ζ

¹ H NMR (400 MH, 06-OMZO, 300K) δ = 9.98 (8, 1H), 8.22 (t, 2H), 7.74 (t, 2H), 7.34 (t, 1H), 7.09 (t, 1H) 6.92 (t, 2H), 5.03 (t, 2H), 3.79 (8, 3H), 3.45 (8, 3H).

Example 11

(gas) ethyl {[(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin-4-yl) methyl] (methyl) oxide-X ⁶ -sulfanylidene} carbamate

To a stirred solution of (rac) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4 - [(δmethylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine (75 mg; 0 , 19 mmol; Example 1) ethyl chloroformate (26 mg; 0.24 mmol) was added dropwise in pyridine (2.0 ml) at 0 ° C. The ice bath was removed and the mixture was stirred for 5 hours at room temperature, and then it was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. To obtain the desired product (24 mg; 0.05 mmol), the residue was purified using preparative HPLC.

System: AUa1sg8 Ai1oriyisa1yup8u81st: Riter 254, 8atr1e Mapadsg 2767, SRO, ϋΑϋ 2996, ΕΕ8ϋ 2424, 3 (2ϋ 3100 Speaker: ХВп§с1е С18 5 μm 100x30 mm Solvent: A = H ₂ O + 0.2% vol. ΝΗ ₃ (32%) B = ΜεΟΝ Gradient: 0-8 min 30-90% B Flow rate: 70 TEU / min Temperature: Room temperature Solution: 59.0 mg / 1.5tEOM8O Volume entered 3 x 0.5 TE samples: Detection: DMD, scanning range 210-400 nm МЗ Ε8Ι +, Ε8Ι-, scanning range 160-1000 ητ / ζ Retention Time Purity (%) (in minutes) 4.6-5.0> 99

¹ H NMR (400 MN / a, and _6- ОМЗО, 300К) δ = 9.90 (8, 1Н), 8.20 (t, 2Н), 7.73 (t, 1Н), 7.68 (8, 1Н), 7.34 (t, 1Н) ), 7.09 (t, 1H), 6.91 (t, 2H), 4.85 (t, 2H), 3.98 (d, 2H), 3.79 (8, 3H), 3.25 (8, 3H), 1.13 (ίτ, 3H) .

- 74 027226

Example 12: (gas) -1-ethyl-3 - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin4-yl) methyl] ( methyl) oxide-X ⁶ -sulfanylidene} urea

To a stirred solution of (rac ^ -fluoroA - ^ - fluoro ^ -methoxyphenyl) ^ - ^ - ^ methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine (75 mg; 0.19 mmol; Example 1) and triethylamine (19 mg; 0.19 mmol) in OMR (2.0 ml) was added ethyl isocyanate (13 mg; 0.19 mmol) at room temperature. The mixture was stirred for 7 hours at room temperature before it was diluted with an aqueous solution of sodium chloride and extracted twice with ethyl acetate. The mixed organic layers were filtered using a Whatman filter and concentrated. To obtain the desired product (24 mg; 0.05 mmol), the residue was purified using preparative HPLC.

System: \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ up OF::: R::: 254: 8Atr1e Mapadeg 2767, SRO, ϋΑϋ 2996, ΡΡδϋ 2424, 8 (D) 3100 Speaker: ХВп§с1е С18 5 mkt 100 x 30 tt Dissolve l: A = H ₂ O + 0.2% vol. ΝΗ ₃ (32%) B = MeOH Gradient: 0-5.5 min 54-59% V Flow rate: 70 ml / min. Temperature: Room temperature Solution: 78 mg / 2 shR ϋΜδΟ / MeOH 1: 1 Volume entered samples: 2 x 1 ml Detection: DMD, scanning range 210-400 nm Μδ ΡδΙ +, ΡδΙ-, scan range 160-1000 ητ / ζ

retention time (in minutes) purity(%) 3.97-4.75 97

¹ N NΜK (400 MN /, ά6- ^ Μ8Θ, 300K) δ = 9.83 (s, 1H), 8.19 (t, 2H), 7.72 (t, 1H), 7.67 (s, 1H), 7.33 (t, 1H ), 7.09 (t, 1H), 6.90 (t, 2H), 6.76 (! G, 1H), 4.81 (t, 2H), 3.79 (s, 3H), 3.10 (s, 3H), 2.97 (t, 2H) ), 0.96 (! G, 3H).

Example 13: (^ ac) -N - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin-4yl) methyl] (methyl) oxide -X ⁶ -sulfanylidene} acetamide

To a stirred solution (rac ^ -fluoroA - ^ - fluoro ^ -methoxyphenyl) ^ - ^ - ^ methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine (75 mg; 0.19 mmol; Example 19) and triethylamine (19 mg; 0.19 mmol) in OSM (2.0 ml) at 0 ° C was added dropwise acetyl chloride (16 mg; 0.20 mmol). The ice bath was removed and the mixture was stirred for 16 hours at room temperature, and then it was diluted with water and extracted twice with ethyl acetate. The mixed organic layers were filtered using a Whatman filter and concentrated. To obtain the desired product (8 mg; 0.02 mmol), the residue was purified using preparative HPLC.

- 75 027226

System: \ Wa1eg8 Au1oripysa1yup8u81esh: Rishr 254, 8atr1e Mapadeg 2767, СРО, ΌΑΌ 2996, ЕЗО 2424, 80Ό 3100 Speaker: HVpdOe C18 5 μm 100x30 mm Solvent b: A = H ₂ O + 0.1% V1. UNSD (99%) B = ΜεΟΝ Gradient: 0-8 min 25-45% B Flow rate: 70 ml / min. Temperature: Room temperature Solution: 68.0 mg / 1.5ηαΕϋΜ8Ο Volume entered 6 x 0.25 gpe

samples: Detection: DMD, scanning range 210-400 nm M3 Ε8Ι +, Ε8Ι-, scanning range 160-1000 t / ζ retention time (in minutes) purity(%) 3.10-4.50 > 99

¹ H NMR (400 M1 Ιζ, -OM8O d _6, 300K) δ = 9.90 (s, 1Η), 8.20 (t, 2Η), 7.73 (m, 1Η), 7.68 (s, 1Η), 7.34 (m, 1Η ), 7.09 (t, 1Η), 6.90 (t, 2Η), 4.84 (t, 2Η), 3.79 (s, 3Η), 3.21 (s, 3Η), 1.93 (s, 3Η).

Example 14: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4 - [(8-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine hydrochloride; enantiomer 2

To a stirred solution of Example 3 (50 mg; 0.12 mmol) in HeCN (6.0 ml) was added a solution of hydrogen chloride in dioxane (4Ν, 0.03 ml; 0.12 mmol), and the sample was stirred for 1 h at room temperature. To obtain the target product (50 mg; 0.11 mmol), the sample was concentrated.

¹ H NMR (500 M1 Ιζ, 6-EM8O, 300K) δ = 8.34 (t, 2Η), 7.68 (s, 1Η), 7.55 (t, 1Η), 7.39 (t, 1Η), 7.21 (t, 1Η) , 7.14 (t, 1Η), 6.95 (t, 1Η), 5.15 (t, 2Η), 3.82 (s, 3Η), 3.47 (s, 3Η).

Example 15: (gas) -ethyl {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6 methoxypyridin-4-yl) methyl] (methyl) oxide-X ⁶ -sulfanylidene} carbamate

Preparation of Intermediate 15.1: 2-chloro-6-methoxy-4 - [(methylsulfanyl) methyl] pyridine

To a stirred solution of 4- (bromomethyl) -2-chloro-6-methoxypyridine (5.00 g; 21.4 mmol) in acetone (250 ml) was added dropwise an aqueous solution of sodium methanethiolate (21%, 7.06 ml, 21 , 1 mmol) when cooled in a water bath at room temperature. The mixture was stirred at room temperature for 150 minutes. Ethyl acetate was added and the layers were separated. The organic layers were washed with a saturated aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (gradient: hexane to hexane / ЕУАс 9: 1) to obtain the desired product (4.06 g; 19.9 mmol).

¹ H NMR (300 M1 Ιζ, CBC1 ₃ , 300K): δ [ppm] = 6.92 (s, 1Η), 6.61 (s, 1Η), 3.96 (s, 3Η), 3.56 (s, 2Η), 2.03 (s ,

3Η).

Preparation of Intermediate 15.2: (gas) -2-chloro-6-methoxy-4 - [(methylsulfinyl) - 76 027226 methyl] pyridine

To a solution of 2-chloro-6-methoxy-4 - [(methylsulfanyl) methyl] pyridine (500 mg; 2.46 mmol) in acetonitrile (6.0 ml) was added iron chloride (III) (12 mg; 0.07 mmol ), and the sample was stirred at 0 ° C for 10 min. In one portion, iodic acid (599 mg; 2.63 mmol) was added and the mixture was stirred for 60 minutes at 0 ° C, and then it was added to a stirred solution of sodium pentasodium thiosulfate (3.41 g; 13.75 mmol) in ice water (71 ml). The sample was saturated with solid sodium chloride and extracted using ethyl acetate and an ESM. The mixed organic layers were filtered using a Whatman filter and concentrated to give the desired product (533 mg; 2.43 mmol).

¹ H NMR (400 MS, O ₆ -PM8O, 300K) δ = 7.03 (δ, 1Η), 6.77 (δ, 1Η), 4.15 (ά, 1Η), 3.93 (ά, 1Η), 3.85 (δ, 3Η) , 3.30 (δ, 3Η).

Preparation of Intermediate 15.3: (gas) -2-chloro-6-methoxy-4 - [(8methylsulfonimidoyl) methyl] pyridine

To a suspension of (rac) -2-chloro-6-methoxy-4 - [(methylsulfinyl) methyl] pyridine (4.30 g; 19.57 mmol), trifluoroacetamide (4.43 g; 39.15 mmol), magnesium oxide (3 , 16 g; 78.30 mmol) and a rhodium acetate (P) dimer (0.22 g; 0.49 mmol) in an ESM (146 ml) at room temperature iodobenzene diacetate (9.46 g; 29.36 mmol) was added. The mixture was stirred for 18 hours at room temperature. The suspension was filtered through celite, and a filtrate concentrate was obtained under reduced pressure. The residue was dissolved in MeOH (1694 ml) in ethanol and potassium carbonate (5.41 g; 39.15 mmol) was added. The mixture was stirred for 90 minutes before it was concentrated under reduced pressure to approximately 150 ml. The sample was diluted with a large amount of THP / EE (1: 1) and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. The residue was redissolved in EJAc / MeOH (1: 1), filtered and concentrated. The residue was purified using silica gel column chromatography (from hexane / ethyl acetate 50% to pure ethyl acetate) to obtain the desired product (2.715 g; 11.55 mmol).

¹ H NMR (400 MIG, O ₆ -PM8O, 300K) δ = 7.15 (t, 1Η), 6.90 (t, 1Η), 4.45 (ά, 1Η), 4.35 (ά, 1Η), 3.89 (δ, 1Η) , 3.85 (δ, 3Η), 2.61 (δ, 3Η).

Preparation of Intermediate 15.4: (gas) -ethyl {[(2-chloro-6-methoxypyridin-4yl) methyl] (methyl) oxide-X ⁶ -sulfanylidene) carbamate

To a stirred solution of (rac) -2-chloro-6-methoxy-4 - [(8-methylsulfonimidoyl) methyl] pyridine (500 mg; 2.13 mmol) in pyridine (10.0 ml) at 0 ° C was added dropwise ethyl chloroformate (0.265 ml; 2.77 mmol). The ice bath was removed and the mixture was stirred overnight at room temperature, and then it was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated to give a crude product (660 mg), which was used without further purification.

¹ H NMR (400 MS, SPS1 ₃ , 300K) δ = 7.00 (t, 1Η), 6.74 (t, 1Η), 4.71 (ά, 1Η), 4.63 (ά, 1Η), 4.20 (ς, 2Η), 3.96 (δ, 3Η), 3.08 (δ, 3Η), 1.34 (ϊγ, 3Η).

Getting the final product.

A mixture of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine (381 mg; 1.61 mmol), (race) -ethyl {[((2-chloro-6-methoxypyridin-4-yl) methyl ] (methyl) oxide-X ⁶ -sulfanylidene} carbamate (330 mg; 1.08 mmol), chlorine (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'-biphenyl) [2- ( 2-aminoethyl) phenyl] palladium (P) methyl tert-butyl ether adduct (89 mg; 0.11 mmol; ABSC OTHI & CO. CO) and 2 (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl (51 mg; 0.11 mmol; Alysu Syetua1 Sotrapu Sch.) and potassium phosphate (1142 mg; 5.38 mmol) in toluene (25 ml) and IMR (3 ml) were stirred in an argon atmosphere at 130 ° C for 2 h. After cooling robe diluted with ethyl acetate / TRR (1: 1) and washed with aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified using silica gel column chromatography (hexane to hexane / ethyl acetate 80%) to obtain a pure product (292 mg; 0.57 mmol).

- 77 027226 ¹ H NMR (400 MH /, ά ₆ - ^ ΜδΟ, 300K) δ = 8.17 (t, 1Η), 7.66 (t, 1Η), 7.29 (t, 1Η), 7.25 (t, 1Η), 7.09 (δ,

1Η), 6.77 (t, 2Η), 6.35 (t, 1Η), 4.68 (t, 2Η), 4.20 (t, 2Η), 3.89 (δ, 3η), 3.85 (δ, 3Η), 3.09 (δ, 3Η ), 1.33 (ΐτ,

3Η).

Example 16: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4 - [(δ-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine hydrochloride; enantiomer 1

To the stirred solution of Example 2 (100 mg; 0.25 mmol) in HeCN (12.0 ml) at room temperature was added a solution of hydrogen chloride in dioxane (4Ν, 0.06 ml; 0.25 mmol). The sample was subjected to ultrasound for 5 minutes, and then the sample was concentrated to obtain the desired product (112 mg; 0.25 mmol).

¹ H NMR (500 MN /, ά ₆ - ^ ΜδΟ, 300K) δ = 8.34 (t, 2Η), 7.68 (δ, 1Η), 7.55 (t, 1Η), 7.39 (t, 1Η), 7.21 (t, 1Η), 7.14 (t, 1Η), 6.95 (t, 1Η), 5.15 (t, 2Η), 3.82 (δ, 3Η), 3.47 (δ, 3Η).

Example 17: (^ ac) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {6-fluoro-4 - [(δ-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2 -amine

Example 18: (^ ac) -2,2,2-trifluoro-N - {[(2-fluoro-6 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methyl] (methyl) oxide-X ⁶ -sulfanylidene} acetamide

Preparation of Intermediate 17.1: (2,6-difluoropyridin-4-yl) methanol

To a stirred solution of 2,6-difluoropyridine-4-carboxylic acid (5.32 g; 32.8 mmol; Ma1p \ 8c1epys, No. CA8 88912-23-6) in ΤΗΡ (85 ml) at 0 ° C was added a 1M solution of the complex borantetrahydrofuran in ΤΗΡ (13.2 ml; 131.2 mmol). The mixture was allowed to react at room temperature overnight. Then, MeOH (15.9 ml) was carefully added to the stirred mixture while cooling in an ice bath. The sample was diluted with ethyl acetate and washed with an aqueous solution of sodium hydroxide (1Ν) and a saturated aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated to give the main compound (4.85 g), which was used without further purification.

¹ H NMR (400 MN /, OM ^ L): δ [ppm] = 7.06 (δ, 2Η), 5.68 (ί, 1Η), 4.62 (ά, 2Η).

Preparation of Intermediate 17.2: (2-amino-fluoropyridin-4-yl) methanol

A mixture of (2,6-difluoropyridin-4-yl) methanol (330 mg; 2.27 mmol) and 33% (by weight) aqueous ammonia (19.8 ml) was placed in a microwave tube. The mixture was allowed to react at 110 ° C. for 6 hours in a hermetically sealed tube under microwave radiation. The mixture was then diluted with water and extracted with ethyl acetate. The mixed organic layers were washed with saturated aqueous sodium chloride and dried over magnesium sulfate. To obtain the main compound (209 mg; 1.41 mmol), the condensation residue was purified by silica gel column chromatography (dichloromethane / methanol).

¹ H NMR (400 MN /, ^ Μ δΟ-ά6): δ [ppm] = 6.28 (άά, 1Η), 6.22 (δ, 2Η), 5.99 (δ, 1Η), 5.28 (ί, 1Η), 4.37 (ά ,

- 78 027226

2Η).

Preparation of Intermediate 17.3: 4- (chloromethyl) -6-fluoropyridin-2-amine

To a stirred solution of (2-amino-6-fluoropyridin-4-yl) methanol (194 mg; 1.36 mmol) in TOC (6.6 ml) and ΝΜΡ (0.44 ml) at 0 ° C was added dropwise thionyl chloride (0.25 ml; 3.41 mmol). The mixture was allowed to react at room temperature overnight. The sample was diluted with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and was extracted three times using ^ CΜ. The mixed organic layers were filtered, dried over sodium sulfate and concentrated. To obtain the desired product (161 mg; 0.94 mmol), the crude material was purified by silica gel column chromatography (dichloromethane / methanol).

¹ H NMR (400 ΜΗζ, ΏΜ8Ο-66): δ [ppm] = 6.45 (δ, 1Η), 6.34 (b, 1Η), 6.13 (δ, 1Η), 4.61 (δ, 2Η).

Preparation of Intermediate 17.4: 6-fluoro-4 - [(methylsulfanyl) methyl] pyridin-2-amine

To a stirred solution of 4- (chloromethyl) -6-fluoropyridin-2-amine (110 mg; 0.67 mmol) in ethanol (5.5 ml) at 0 ° C was added sodium methanethiolate (99 mg; 1.34 mmol). The cold bath was removed and the sample was stirred at room temperature for 3 hours. The sample was diluted with saturated aqueous sodium chloride and extracted twice with ethyl acetate.

The mixed organic layers were washed with water, dried (sodium sulfate), filtered and concentrated to obtain the desired product (117 mg).

¹ H NMR (400 ΜΗζ, ΏΜ8Ο-6 ₆ ): δ [ppm] = 6.29 (δ, 2Η), 6.24 (b, 1Η), 6.04 (δ, 1Η), 3.54 (δ, 2Η), 1.97 (δ,

3Η).

Preparation of Intermediate 17.5: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) - ^ {6-fluoro-4 [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine

A mixture of 6-fluoro-4 - [(methylsulfanyl) methyl] pyridin-2-amine (95 mg; 0.57 mmol), 2-chloro-5-fluoro-4- (4 fluoro-2-methoxyphenyl) pyridine (217 mg; 0.8 mmol; intermediate 1.1), chlorine (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1, G-biphenyl) [2- (2-aminoethyl) phenyl] palladium (P) methyl tert-butyl ether adduct ( 44 mg; 0.054 mmol; ABSC OTN & Co. KO) and 2 (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl (25.6 mg; 0.054 mmol; A1bcb Chlorea1 Sotrapa Sch.) And potassium phosphate (570 mg ; 2.68 mmol) in toluene (12.1 ml) and ΝΜΡ (0.94 ml) were stirred under argon at 130 ° C for 3 hours. After cooling, the sample was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. To obtain the main compound (174 mg; 0.44 mmol), the residue was purified by silica gel column chromatography (hexane / ethyl acetate).

¹ H NMR (400 ΜΗζ, ΏΜδΟ-bb): δ [ppm] = 10.02 (δ, 1Η), 8.27 (b, 1η), 7.60-7.55 (t, 2Η), 7.36 (bb, 1Η), 7.11 (bb , 1Η), 6.93 (1gb, 1Η), 6.51 (δ, 1Η), 3.81 (δ, 3Η), 3.70 (δ, 2Η), 2.02 (δ, 3Η).

Preparation of Intermediate 17.6: (gas) -2,2,2-trifluoro - ^ {[(2-fluoro-6 - {[5-fluoro-4- (4 fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin-4-yl) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide

Under argon, a solution of 2,2,2-trifluoroacetamide (60 mg; 0.51 mmol) in dioxane (1 ml) was added dropwise to a solution of sodium tert-butoxide (25.3 mg; 0.25 mmol) in dioxane (1 ml), so that the temperature of the mixture does not exceed 10 ° C. Then, a fresh solution of 1,3-dibromo-5,5-dimethylhydantoin (55 mg; 0.19 mmol) in dioxane (1 ml) was added dropwise to the stirred mixture, so that the temperature

- 79 027226 of the mixture did not exceed 10 ° C. The mixture was then stirred for 10 minutes under normal temperature conditions. Finally, a solution of 5-fluoro-4- (4-fluoro-2methoxyphenyl) -Y- {6-fluoro-4 - [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine was added dropwise to the stirred mixture. (100 mg; 0.25 mmol) in dioxane (1 ml). The mixture was stirred for 30 minutes. The sample was diluted with ethyl acetate and an aqueous solution of sodium sulfite (10%) was added. The sample was extracted three times with ethyl acetate. The mixed organic layers were washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. To obtain the main compound (52 mg; 0.1 mmol), the residue was purified by silica gel column chromatography (hexanes / ethyl acetate).

¹ H NMR (400 MH /, ^ M8O-ά ₆ ): δ [ppm] = 10.19 (δ, 1H), 8.24 (ά, 1H), 7.68 (δ, 1H), 7.52 (ά, 1H), 7.36 ( άά, 1H), 7.11 (άά, 1H), 6.93 (ίά, 1H), 6.52 (δ, 1H), 4.65-4.43 (t, 2H), 3.81 (δ, 3H), 2.81 (δ, 3H).

Getting the final products.

(rac) -2,2,2-trifluoro-L - {[(2-fluoro-6 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4- il) methyl] (methyl) -X ⁴ -sulfanylidene} acetamide (318 mg, 0.63 mmol) was dissolved in methanol (25 ml). Water (0.66 ml) was added to this solution. A solution of Ohope® (331 mg: 0.538 mmol) in water (2 ml) was added to the first solution, and the resulting mixture was stirred. The pH value was adjusted in the range of 6.8–7.2 by adding an aqueous solution of potassium hydroxide (5%). After 100 minutes of reaction time, an additional amount of Ohope® (156 mg; 0.253 mmol) was added. The pH value was adjusted in the range of 7.8–8.2. After an additional 20 minutes of stirring, the sample was diluted with water (300 ml). The suspension was extracted using ethyl acetate. The organic layer was washed with an aqueous solution of sodium sulfite (10%), dried over magnesium sulfate, filtered and concentrated. To obtain (race) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-fluoro-4 - [(8-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine (66 mg; 0.16 mmol; Example 17) and (race) -2,2,2-trifluoro-L - {[(2-fluoro6 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) ) pyridin-2-yl] amino} pyridin-4-yl) methyl] (methyl) oxide-X ⁶ sulfanilidene} acetamide (126 mg; 0.24 mmol; Example 18), the residue was purified by silica gel column chromatography (ethyl acetate / methanol).

Example 17:

¹ H NMR (400 MH /, ^ M8O-ά ₆ ): δ [ppm] = 10.09 (δ, 1H), 8.25 (ά, 1H), 7.63 (δ, 1H), 7.58 (ά, 1H), 7.36 ( άά,

1H), 7.11 (άά, 1H), 6.93 (! Τά, 1H), 6.62 (δ, 1H), 4.44 (δ, 2H), 3.84 (δ, 1H), 3.81 (δ, 3H), 2.90 (δ, 3H).

Example 18:

¹ H NMR (400 MN /, BM 8 O ^): δ [ppm] = 10.24 (δ, 1H), 8.24 (ά, 1H), 7.77 (δ, 1H), 7.53 (ά, 1H), 7.36 (άά,

1H), 7.11 (άά, 1H), 6.93 (! Τά, 1H), 6.61 (δ, 1H), 5.16 (δ, 2H), 3.81 (δ, 3H), 3.55 (δ, 3H).

Examples 19 and 20: enantiomers of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-fluoro-4 - [(8methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine

(rac) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-fluoro-4 - [(8-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine (example 17 , 178 mg) were separated into individual enantiomers by preparative chiral HPLC.

System: Αβίΐεηί: Rger 1200, 2xRger Rishr, OBA, Μλл, Slop: Schrn! Napspeg 215 Speaker: S1Lga1rak ΙΑ 5 μm 250x20 mm Solvent: MESA / ethanol / diethylamine 90: 10: 0.1 (volume content) Speed flow: 25 ml / min.

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Temperature: Room temperature Solution: 178 mg / 6 ml ESM / Meon Volume entered samples: 10 x 0.6 ml Detection: UV, 254 nm. Time retention (in min.) purity (%) exit specific optical rotation: Example 19 Enantiomer 1 4.4-5.7 82.5 32 mg (0.07 mmol) [α] _ο ^2υ = 12.6 ° +/- 0.15 ° (EM8O, 589 pt, 20 ° C). Example 20 Enantiomer 2 5.7-8.4 97.2 70 mg (0.16 mmol) [α] ο ^2υ = -12.9 ° +/- 0.25 ° (EMZO, 589 ps, 20 ° C).

Example 21: (^ ac) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4 - [(8-methylsulfonimidoyl) methyl] -6 (trifluoromethyl) pyridin-2-yl} pyridin- 2-amine

Preparation of (trifluoromethyl) pyridine

2-chloro-4 - [(methylsulfanyl) methyl] -6K to a stirred solution of 2-chloro-4- (chloromethyl) -6- (trifluoromethyl) pyridine (490 mg; 1.18 mmol; AcfBet bC; No. CA8 1196154-47- 8) in methanol (15 ml) at 0 ° С sodium methanethiolate (254 mg; 3.6 mmol) was added. The cold bath was removed and the sample was stirred at room temperature for 3 hours. The sample was diluted with saturated aqueous sodium chloride and extracted twice with ethyl acetate. The mixed organic layers were washed with water, dried (sodium sulfate), filtered and concentrated to give a crude product. Purification by silica gel column chromatography (hexanes / ethyl acetate) gave the main compound (446 mg; 1.68 mmol).

¹ H NMR (400 MH /, EM8O-b ₆ ): δ [ppm] = 7.91 (s, 1H), 7.82 (s, 1H), 3.84 (s, 2H), 1.97 (s, 3H).

Preparation of Intermediate 21.2: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4 [(methylsulfanyl) methyl] -6- (trifluoromethyl) pyridin-2-yl} pyridin-2-amine

A mixture of 2-chloro-4 - [(methylsulfanyl) methyl] -6- (trifluoromethyl) pyridine (246 mg; 0.38 mmol;), 5-fluoro4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine ( 157 mg; 0.66 mmol; intermediate 4.1), chlorine (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1, G-biphenyl) [2- (2-aminoethyl) phenyl] palladium (P) methyl tert- butyl ether adduct (31.1 mg; 0.038 mmol; ABSC OTN & CO. KO) and 2 (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl (17.9 mg; 0.038 mmol; A1bpsB S.Betuia1 Sotrapa ^ s.) and potassium phosphate (400 mg; 1.88 mmol) in toluene (10 ml) and NMR (1 ml) were stirred under argon at 130 ° C for 180 minutes. After cooling, the sample was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. To obtain the main compound (160 mg; 0.36 mmol), the residue was purified by silica gel column chromatography (hexanes / ethyl acetate).

- 81 027226 ¹ H NMR (400 ΜΗζ, ϋΜδΟ-φ,): δ [ppm] = 10.23 (s, 1H), 8.28 (b, 1H), 7.87 (s, 1H), 7.79 (b, 1H), 7.34 (bb,

1H), 7.28 (s, 1H), 7.11 (bb, 1H), 6.93 (1gb, 1H), 3.80 (s, 3H), 3.77 (s, 2H), 2.01 (s, 3H).

Preparation of Intermediate 21.3: (gae) -2,2,2-trifluoro-L - [{[2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} -6- (trifluoromethyl) pyridin-4-yl] methyl} (methyl) -X ⁴ sulfanilidene] acetamide

To a solution of sodium tert-butoxide (42.4 mg; 0.42 mmol) in dioxane (1.5 ml) was added dropwise a solution of 2,2,2-trifluoroacetamide (99.8 mg; 0.86 mmol) in dioxane ( 1.5 ml). Then, a fresh solution of 1,3-dibromo-5,5-dimethylhydantoin (122.4 mg; 0.43 mmol) in dioxane (2 ml) was added dropwise to the stirred mixture. The mixture was then stirred for 10 minutes under normal temperature conditions. Finally, a solution of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y {4 - [(methylsulfanyl) methyl] -6- (trifluoromethyl) pyridin-2-yl} pyridine- was added dropwise to the stirred mixture. 2-amine (225 mg; 0.43 mmol) in dioxane (2 ml). The mixture was stirred for 1 hour. The sample was diluted with ethyl acetate and an aqueous solution of sodium sulfite (10%) was added. The sample was extracted three times with ethyl acetate. The mixed organic layers were washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. To obtain the main compound (123 mg; 0.22 mmol), the residue was purified by silica gel column chromatography (hexanes / ethyl acetate).

¹ H NMR (400 ΜΗζ, ΌΜ3Ο-6 ₆ ): δ [ppm] = 10.40 (s, 1H), 8.26 (b, 1H), 8.00 (s, 1H), 7.71 (b, 1H), 7.35 (bb, 1H), 7.23 (b, 1H), 7.11 (bb, 1H), 6.93 (1gb, 1H), 4.80-4.45 (t, 2H), 3.80 (s, 3H), 2.82 (s, 3H).

Intermediates 21.4 and 21.5: enantiomers (rac) -2,2,2-trifluoro-L - [{[2 - {[5-fluoro-4- (4-fluoro2-methoxyphenyl) pyridin-2-yl] amino} - 6- (trifluoromethyl) pyridin-4-yl] methyl} (methyl) -X ⁴ sulfanilidene] acetamide; (rac) -2,2,2-trifluoro-L - [{[2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} -6- (trifluoromethyl) pyridine- 4-yl] methyl} (methyl) -X ⁴ -sulfanylidene] acetamide (638 mg) was separated into individual enantiomers by preparative chiral HPLC.

System: Αβΐΐεηΐ: Rger 1200, 2xRger Richard, ϋΡΑ, M \ UE, Rger RS, Speaker: Syga1rak Αϋ-Η 5 μm 250x30 mm Solvent: Hexane / Ethanol 70:30 (volume content) Speed flow: 50 ml / min. Temperature: Room temperature Solution: 638 mg / 8 ml MeOH, Volume entered samples: 23 x 0.35 ml Detection: UV, 254 nm. retention time (in minutes) purity (%) exit specific optical rotation: Intermediate substance 21.4 Enantiomer 1 10.26-11.50 98.59 178 mg (0.31 mmol) [α] _ο ^2υ = 110.1 ° +/- 0.13 ° (ϋΜδΟ, 589 pt, 20 ° C). Intermediate substance 21.5 Enantiomer 2 12.63-14.15 97.27 137 mg (0.25 mmol) Mo ²ⁱ = - 116.3 ° +/- 0.08 ° (ϋΜδΟ, 589 psi, 20 ° C).

Intermediate 21.4, (+) - enantiomer of intermediate 21.3:

¹ H NMR (400 ΜΗζ, ΌΜ3Ο-6 ₆ ): δ [ppm] = 10.40 (s, 1H), 8.26 (b, 1H), 8.00 (s, 1H), 7.71 (b, 1H), 7.35 (bb,

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1H), 7.23 (s, 1H), 7.11 (bb, 1H), 6.93 (! GB, 1H), 4.76-4.47 (t, 2H), 3.80 (s, 3H), 2.82 (s, 3H), 2.08 ( s, 2H).

Intermediate 21.5, (+) - enantiomer of intermediate 21.3:

¹ H NMR (400 MH /, BM8O-b ₆ ): δ [ppm] = 10.40 (s, 1H), 8.26 (b, 1H), 8.00 (s, 1H), 7.71 (b, 1H), 7.35 (bb ,

1H), 7.23 (b, 1H), 7.11 (bb, 1H), 6.93 (! GB, 1H), 4.77-4.46 (t, 2H), 3.80 (s, 3H), 2.82 (s, 3H).

Getting the final product.

The pH of the solution (rac) -2,2,2-trifluoro-X - [{[2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} -6- (trifluoromethyl ) pyridin-4-yl] methyl} (methyl) A ⁴ -sulfanylidene] acetamide (122 mg; 0.22 mmol; intermediate 21.3) in a mixture of methanol (3.6 ml) / water (0.32 ml) was adjusted to 10.5 by adding an aqueous solution of potassium hydroxide (10%). Ohope® (115 mg; 0.187 mmol) was added. The resulting mixture was stirred for 90 minutes. The pH value was adjusted in the range of 10-11, if necessary, by adding an aqueous solution of potassium hydroxide (10%). An additional amount of Ohope® (34 mg; 0.055 mmol) was added and the mixture was stirred at a pH in the range of 10-11 for 60 minutes. Then the sample was neutralized, diluted with water (40 ml) and extracted using BSM. The mixed organic layers were washed with an aqueous solution of sodium sulfite (10%), dried over magnesium sulfate and concentrated. To obtain the main compound (43 mg; 0.09 mmol), the residue was purified by silica gel column chromatography (ethyl acetate / methanol).

¹ H NMR (400 MH, OM8O-b6): δ [ppm] = 10.31 (s, 1H), 8.27 (b, 1H), 7.96 (s, 1H), 7.77 (b, 1H), 7.39 (b, 1H), 7.35 (bb, 1H), 7.11 (bb, 1H), 6.93 (! B, 1H), 4.52 (s, 2H), 3.89 (s, 1H), 3.80 (s, 3H), 2.91 (s, 3H).

Examples 22 and 23: enantiomers of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -X- {4 - [(8methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2-yl} pyridin-2-amine

B

(rac) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -X- {4 - [(8-methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2-yl} pyridin-2-amine (example 21) was divided into individual enantiomers by preparative chiral HPLC.

System: Αβίΐεηί: Rger 1200, 2xRger Riter, EA, MAE, Rger RS Speaker: Syga1rak GO 5 μm 250x30 mm No. 022 Solvent: Hexane / 2-propanol / diethylamine 70: 30: 0.1 (volume content) Flow rate: 50 ml / min. Temperature: Room temperature Solution: 3 80 mg / 5.6 mg ESM / MeOH 1: 1 Volume entered samples: 6 x 0.93 ml Detection: UV, 280 nm Time retention (in minutes) purity (%) exit specific optical rotation: Example 22 Enantiomer 1 10.5-12.8 > 99.9% 105 mg (0.21 mmol) [а] _о ²⁰ = 16.6 ° +/- 0.15 ° (EMZO, 589 ps, 20 ° С). Example 23 Enantiomer 2 13.1-16.7 98.9% 115 mg (0.23 mmol) [a] _о ²¹⁾ = -14.7 ° +/- 0.15 ° (EMZO, 589 psi, 20 ° С).

Example 22, (-) - enantiomer:

¹ H NMR (400 MH, OM8O-b6): δ [ppm] = 10.31 (s, 1H), 8.27 (b, 1H), 7.96 (s, 1H), 7.77 (b, 1H), 7.39 (s, 1H), 7.35 (bb, 1H), 7.11 (bb, 1H), 6.93 (! B, 1H), 4.52 (s, 2H), 3.90 (s, 1H), 3.80 (s, 3H), 2.91 (s, 3H).

Example 23, (-) - enantiomer:

¹ H NMR (400 MH, OM8O-b6): δ [ppm] = 10.31 (s, 1H), 8.27 (b, 1H), 7.96 (s, 1H), 7.77 (b, 1H), 7.39 (s, 1H), 7.35 (bb, 1H), 7.11 (bb, 1H), 6.93 (! B, 1H), 4.52 (s, 2H), 3.90 (s, 1H), 3.80 (s, 3H), 2.91 (s, 3H).

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Alternative preparation of Example 22: (+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -X- {4 - [(8methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2-yl} pyridine -2-amine

Example 24: (+) - 2,2,2-trifluoro-X - [{[2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6 ( trifluoromethyl) pyridin-4-yl] methyl} (methyl) oxide-X ⁶ -sulfanylidene] acetamide

Examples 22 and 24 were obtained under conditions similar to those described for the preparation of Examples 17 and 18 using (+) - 2,2,2-trifluoro-X - [{[2 - {[5-fluoro-4- ( 4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} -6- (trifluoromethyl) pyridin-4-yl] methyl} (methyl) -X ⁴ sulfanylidene] acetamide (175 mg; 0.3 mmol; intermediate 21.4) . Silica gel column chromatography (ethyl acetate / methanol) gave (+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) X- {4 - [(3-methylsulfonimidoyl) methyl] -6- (trifluoromethyl ) pyridin-2-yl} pyridin-2-amine (94 mg; 0.2 mmol; Example 22) and (+) - 2,2,2-trifluoro-X - [{[2 - {[5-fluoro- 4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} 6- (trifluoromethyl) pyridin-4-yl] methyl} (methyl) oxide-X ⁶ -sulfanylidene] acetamide (20 mg; 0.03 mmol example 24).

¹ H NMR (400 MH /, PMZO-Y6): δ [ppm] = 10.46 (δ, 1H), 8.26 (1, 1H), 8.10 (δ, 1H), 7.72 (1, 1H), 7.377.32 ( t, 2H), 7.11 (11, 1H), 6.93 (1g1, 1H), 5.29-5.20 (t, 2H), 3.81 (δ, 3H), 3.59 (δ, 3H).

Alternative preparation of Example 23: (-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -X- {4 - [(8methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2-yl} pyridine -2-amine

Example 25: (-) - 2,2,2-trifluoro-X - [{[2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6 ( trifluoromethyl) pyridin-4-yl] methyl} (methyl) oxide-X ⁶ -sulfanylidene] acetamide

Examples 23 and 25 were obtained under conditions similar to those described for the preparation of Examples 17 and 18 using (-) - 2,2,2-trifluoro-X - [{[2 - {[5-fluoro-4- ( 4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} -6- (trifluoromethyl) pyridin-4-yl] methyl} (methyl) -X ⁴ sulfanylidene] acetamide (165 mg; 0.295 mmol; intermediate 21.5). Silica gel column chromatography (ethyl acetate / methanol) gave (-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) X- {4 - [(3-methylsulfonimidoyl) methyl] -6- (trifluoromethyl ) pyridin-2-yl} pyridin-2-amine (85 mg; 0.18 mmol; Example 23) and (-) - 2,2,2-trifluoro-X - [{[2 - {[5-fluoro- 4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} 6- (trifluoromethyl) pyridin-4-yl] methyl} (methyl) oxide-X ⁶ -sulfanylidene] acetamide (5 mg; 0.008 mmol example 25).

¹ H NMR (400 MN /, PMZO-16): δ [ppm] = 10.46 (δ, 1H), 8.26 (1, 1H), 8.10 (δ, 1H), 7.72 (1, 1H), 7.387.31 ( t, 2H), 7.11 (11, 1H), 6.93 (1g1, 1H), 5.28-5.19 (t, 2H), 3.80 (δ, 4H), 3.59 (δ, 3H).

Example 26: (gas) -4- (2-ethoxy-4-fluorophenyl) -5-fluoro-Ν - {6-fluoro-4 - [(3-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2 - amine

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Example 27: (gas) -X- {[(2- {[4- (2-ethoxy-4-fluorophenyl) -5-fluoropyridin-2-yl] amino} -6-fluoropyridin-4yl) methyl] (methyl) oxide-X ⁶ -sulfanylidene} -2,2,2-trifluoroacetamide

Preparation of Intermediate 26.1: 2-chloro-4- (2-ethoxy-4-fluorophenyl) -5-fluoropyridine

Intermediate 26.1 was obtained under similar conditions as described in the preparation of intermediate 1.1 using 2-chloro-5-fluoro-4-iodopyridine (Mapseyek Ogdashsk, No. CA8 884494-49-9) and (2-ethoxy-4-fluorophenyl) boronic acid (ABSC, No. CA8 480438-58-2).

¹ H NMR (400 MP /, OM8O-b ₆ ): δ [ppm] = 8.49 (b, 1Η), 7.61 (b, 1Η), 7.42 (bb, 1Η), 7.10 (bb, 1Η), 6.92 (1 gb) , 1Η), 4.10 (ς, 2Η), 1.23 (1d, 3Η).

Preparation of Intermediate 26.2: 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {6-fluoro-4 [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine

Intermediate 26.2 was obtained under similar conditions as described in the preparation of intermediate 17.5 using 6-fluoro-4 - [(methylsulfanyl) methyl] pyridin-2-amine (intermediate 17.4) and 2-chloro-4- (2-ethoxy -4-fluorophenyl) -5-fluoropyridine.

¹ H NMR (400 MP /, OM8O-b ₆ ): δ [ppm] = 10.03 (q, 1Η), 8.27 (b, 1Η), 7.63 (b, 1Η), 7.57 (q, 1Η), 7.35 (bb , 1Η), 7.09 (bb, 1Η), 6.91 (1gb, 1Η), 6.51 (k, 1Η), 4.10 (d, 2Η), 3.70 (k, 2Η), 2.02 (k, 3Η), 1.24 (1g, 3Η).

Preparation of Intermediate 26.3: (gas) -X - [[(2 - {[4- (2-ethoxy-4-fluorophenyl) -5 fluoropyridin-2-yl] amino} -6-fluoropyridin-4-yl) methyl] ( methyl) -X ⁴ -sulfinylidene] -2,2,2 trifluoroacetamide

Intermediate 26.3 was obtained under similar conditions as described in the preparation of intermediate 17.6 using 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {6-fluoro-4 [(methylsulfanyl) methyl] pyridin-2 -yl} pyridin-2-amine.

¹ H NMR (400 MP /, PM8O-b6): δ [ppm] = 10.20 (q, 1Η), 8.25 (b, 1Η), 7.68 (q, 1Η), 7.56 (b, 1Η), 7.36 (bb, 1Η), 7.09 (bb, 1Η), 6.91 (1gb, 1Η), 6.51 (q, 1Η), 4.66-4.44 (t, 2Η), 4.10 (d, 2Η), 2.81 (q, 3Η), 1.27-1.22 (t, 5Η).

Getting the final products.

Examples 26 and 27 were obtained under conditions similar to those described for the preparation of Examples 17 and 18 using (rac) -N - [[(2 - {[4- (2-ethoxy-4-fluorophenyl) -5-fluoropyridine -2yl] amino} -6-fluoropyridin-4-yl) methyl] (methyl) -X ⁴ -sulfinylidene] -2,2,2-trifluoroacetamide.

Example 26:

¹ H NMR (400 MH /, OM8O-b ₆ ): δ [ppm] = 10.10 (q, 1Η), 8.26 (b, 1Η), 7.65-7.59 (t, 2Η), 7.36 (bb, 1Η), 7.09 (bb, 1Η), 6.91 (1gb, 1Η), 6.62 (k, 1Η), 4.44 (k, 2Η), 4.11 (d, 2Η), 3.84 (k, 1Η), 2.90 (k, 3Η), 1.25 ( 1g, 3Η).

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Example 27:

¹ H NMR (400 M1 Ιζ. EM8O-0 ₆ ): δ [ppm] = 10.25 (s, 1H), 8.24 (ά, 1H), 7.77 (s, 1H), 7.57 (ά, 1H), 7.36 (άά , 1H), 7.09 (άά, 1H), 6.91 (ΐίά, 1H), 6.61 (s, 1H), 5.16 (s, 2H), 4.10 (ς, 2H), 3.55 (s, 3H), 1.24 (ϊγ, 3H).

Examples 28 and 29: enantiomers of 4- (2-ethoxy-4-fluorophenyl) -5-fluoro-No. {6-fluoro-4 - [(8methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine

(rac) -4- (2-ethoxy-4-fluorophenyl) -5-fluoro - ^ {6-fluoro-4 - [(8-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine (95 mg, example 26) was divided into individual enantiomers by preparative chiral HPLC.

System: Αβίΐεηί: Rger 1200, 2xRger Richard, OBA, M \ UE, Rger RS, Speaker: Syga1rak ΙΑ 5 μm 250x20 mm Solvent: acetonitrile / ethanol 90:10 (volume content) + 0.1% EEA Flow rate: 31 ml / min. Temperature: Room temperature Solution: 95 mg / 2 ml Meon Volume entered samples: 7 x 0.3 ml Detection: UV, 254 nm. Time retention (in min.) purity (%) exit specific optical rotation: Example 28 Enantiomer 1 3.0-6.0 96.1 35 mg (0.08 mmol) [α] ο ^2υ = 6.3 ° (ϋΜδΟ, 589 pt, 20 ° C). Example 29 Enantiomer 2 8.0-16.0 96.5 25 mg (0.06 mmol) [α] _ο ^2υ = -10.7 ° (ϋΜδΟ, 589 psi, 20 ° C).

Example 28, (-) - enantiomer:

¹ H NMR (400 MS. EM8OSCH ₆ ): δ [ppm] = 10.10 (s, 1H), 8.26 (s, 1H), 7.66-7.59 (t, 2H), 7.36 (ϊγ, 1H), 7.08 (άά, 1H), 6.91 (ϊίά, 1H), 6.62 (s, 1H), 4.44 (s, 2H), 4.10 (ς, 2H), 3.85 (bg.s., 1H), 2.90 (s, 3H), 1.24 ( ϊ γ, 3H).

Example 29, (-) - enantiomer:

¹ H NMR (400 M1 Ιζ. EM8O ^): δ [ppm] = 10.10 (s, 1H), 8.26 (ά, 1H), 7.66-7.59 (t, 2H), 7.40-7.32 (t, 1H), 7.09 (άά, 1H), 6.91 (ΪΓά, 1H), 6.62 (s, 1H), 4.44 (s, 2H), 4.10 (ς, 2H), 3.84 (s, 1H), 2.90 (s, 3H), 1.24 ( ϊ γ, 3H).

Example 30: (gas) -№ {4 - [(8-ethylsulfonimidoyl) methyl] pyridin-2-yl} -5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-amine

Preparation of Intermediate 30.1: No. {4 - [(ethylsulfanyl) methyl] pyridin-2-yl} -5 fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine

Intermediate 30.1 was obtained under similar conditions as described in the preparation of intermediate 17.5 using 4 - [(ethylsulfanyl) methyl] pyridin-2-amine (purchased from Eppat) and 2-chloro-5-fluoro-4- (4- fluoro-2-methoxyphenyl) pyridine (intermediate

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1.1).

¹ H NMR (400 MH /, PM8O-a ₆ ): δ [ppm] = 9.73 (s, 1H), 8.22 (ά, 1H), 8.10 (ά, 1H), 7.81 (ά, 1H), 7.54 (s , 1H), 7.34 (άά, 1H), 7.09 (άά, 1H), 6.95-6.88 (t, 1H), 6.81 (άά, 1H), 3.80 (s, 3H), 3.68 (s, 2H), 2.45 ( ς, 2H), 1.18 (! g, 3H).

Preparation of Intermediate 30.2: (gas) - ^ {Ethyl [(2 - {[5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-yl] amino} pyridin-4-yl) methyl] -X ⁴ -sulfanylidene} -2,2,2-trifluoroacetamide

Intermediate 30.2 was obtained under similar conditions as described in the preparation of intermediate 17.6 using ^ {4 - [(ethylsulfanyl) methyl] pyridin-2-yl} -5-fluoro-4- (4 fluoro-2-methoxyphenyl) pyridin-2 -Amina.

¹ H NMR (400 MH, PM8O-66): δ [ppm] = 9.90 (s, 1H), 8.23-8.17 (t, 2H), 7.72 (ά, 1H), 7.67 (s, 1H), 7.35 ( άά, 1H), 7.10 (άά, 1H), 6.92 (! ίά, 1H), 6.83 (άά, 1H), 4.58-4.37 (t, 2H), 3.80 (s, 3H), 3.30-3.22 (t, 1H) ), 3.123.01 (t, 1H), 1.27 (! G, 3H).

Getting the final product.

Example 30 was obtained under conditions similar to those described for the preparation of Example 21 using (race) -№ {ethyl [(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4-yl) methyl] -X ⁴ -sulfanylidene} -2,2,2-trifluoroacetamide.

¹ H NMR (400 MN, PM8O-6 ₆ ): δ [ppm] = 9.80 (s, 1H), 8.21 (ά, 1H), 8.16 (ά, 1H), 7.79 (ά, 1H), 7.60 (s , 1H), 7.35 (άά, 1H), 7.10 (άά, 1H), 6.95-6.88 (t, 2H), 4.36-4.25 (t, 2H), 3.80 (s, 3H), 3.68 (s, 1H), 2.97 (ς, 2H), 1.25 (!, 3H).

Example 31: (gas) -№- {6- (difluoromethyl) -4 - [(8-methylsulfonimidoyl) methyl] pyridin-2-yl} -5-fluoro-4 (4-fluoro-2-methoxyphenyl) pyridin-2 -amine

Preparation of Intermediate 31.1: (gas) -2-chloro-6- (difluoromethyl) -4 - [(methylsulfinyl) methyl] pyridine

To a solution of 2-chloro-4 - [(methylsulfanyl) methyl] pyridine (500 mg, 2.88 mmol; ichrOg§8up! Ex1.3! Ηιη. CE. 8 Oct. 2012, 134, 1494) (1702 mg; 5.76 mmol) in trichloroacetic acid (10.0 ml) and water (4.0 ml) at room temperature added trifluoroacetic acid (0.22 ml; 2 , 88 mmol), then tert-butyl hydroperoxide (70% solution in water; 1.23 ml; 8.64 mmol) was slowly added with vigorous stirring. After 24 hours, the second part of OPM8 (1702 mg; 5.76 mmol) and tert-butyl hydroperoxide (70% solution in water; 1.23 ml; 8.64 mmol) were added, and the sample was stirred for 22 h at room temperature. The reaction mixture was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer was separated and the aqueous was extracted twice using HCM. The mixed organic layers were filtered using a Whatman filter and concentrated. To obtain the desired product (130 mg; 0.54 mmol), the residue was purified by silica gel column chromatography (ESM / EUN 95: 5).

¹ H NMR (300 MH, SPS1 ₃ , 300K): δ = 7.53 (s, 1H), 7.46 (s, 1H), 6.82 (! G, 1H), 4.05 (ά, 1H), 3.91 (ά, 1H) ), 2.60 (s, 3H).

Preparation of Intermediate 31.2: (gas) -№ - [{[2-chloro-6- (difluoromethyl) pyridin-4yl] methyl} (methyl) oxide-X ⁶ -sulfinylidene] -2,2,2-trifluoroacetamide

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To the suspension of (rac) -2-chloro-6- (difluoromethyl) -4 - [(methylsulfinyl) methyl] pyridine (124 g; 0.52 mmol), trifluoroacetamide (117 g; 1.04 mmol), magnesium oxide (83 mg; 2.07 mmol) and a rhodium acetate dimer (P) (6 mg; 0.01 mmol) in an ESM (3 ml) at room temperature, iodobenzene diacetate (250 mg; 0.78 mmol) was added. The mixture was stirred for 18 hours at room temperature. The suspension was filtered through celite, and a filtrate concentrate was obtained under reduced pressure. To obtain the desired product (77 mg; 0.22 mmol), the residue was purified by silica gel column chromatography (from ESM to ESM / JUN 95: 5).

¹ H NMR (400 MI /, SPS1 ₃ , 300K) δ = 7.65 (δ, 1Η), 7.56 (δ, 1Η), 6.64 (1g, 1Η), 4.88 (ά, 1Η), 4.72 (ά, 1Η), 3.35 (δ, 3Η).

Getting the final product.

Mixture of (gas) ^ - [{[2-chloro-6- (difluoromethyl) pyridin-4-yl] methyl} (methyl) oxide-A ⁶ -sulfinylidene] 2,2,2-trifluoroacetamide (72.0 mg; 0 , 21 mmol;), 5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-amine (72.7 mg; 0.31 mmol; intermediate 4.1), chlorine (2-dicyclohexylphosphino-2 ' 4 ', 6'-triisopropyl-1,1'-biphenyl) [2- (2-aminoethyl) phenyl] palladium (P) methyl tert-butyl ether adduct (17.0 mg; 0.02 mmol; ABSC OTI & CO KO) and 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl (9.8 mg; 0.02 mmol; AMpsy Syetua1 Sotrapu Sch.) and potassium phosphate (218 mg; 1.03 mmol) toluene (4.8 ml) and NMR (0.6 ml) were stirred under arg it was at 130 ° C for 2 hours. After cooling, the sample was diluted with ESM and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. To obtain the target product (3.4 mg; 0.01 mmol). the residue was purified using preparative thin layer chromatography.

¹ H NMR (400 MI /, EM8О- ₆ ): δ [ppm] = 8.18 (δ, 1Η), 7.86 (δ, 1Η), 7.50 (t, 2Η), 7.30 (t, 1Η), 7.21 (δ , 1Η), 6.80 (t, 2Η), 6.51 (1g, 1Η), 4.43 (ά, 1Η), 4.31 (ά, 1Η), 3.86 (δ, 3Η), 3.05 (δ, 3Η), 2.87 (bg, 1Η).

Examples 32 and 33: enantiomers of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) - ^ {6-methyl-4 - [(8methylsulphonimidoyl) methyl] pyridin-2-yl} pyr idin-2-amine

mg of racemic 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -X- {6-methyl-4 - [(8methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine (Example 4) was separated with using preparative chiral HPLC.

System: Αβίΐεηί: Rger 1200, 2xRger Richard, OBA, M \ UE, Rger RS Speaker: Sygafak 1C5 μm 250x30 mm, No. 009 Solvent: hexane / 2-propanol / diethylamine 70: 30: 0.1 (volume content) Flow rate: 50 ml / min. Temperature: Room temperature Solution: 86 mg / 2 ml OSM / MeOH 1: 1 Volume entered samples: 2 x 1.0 ml Detection: UV, 280 nm Fractions Time retention (in minutes) purity (%) exit Specific optical rotation: Example 32 Enantiomer 1 17.0-18.8 min > 99.9% 28 mg (0,067 mmol) [αφ ^2υ = + 15.1 ° (1.00, ϋΜδΟ) Example 33 Enantiomer 2 20.8 - 23.0 min > 99.9% 30 mg (0,072 mmol) [αφ ^2θ = -11.6 ° (1.00, ϋΜδΟ)

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Example 32: (+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(δ-methylsulBphonimidoyl) methyl] pyridin-2-yl} pyridin-2- amine

¹ H NMR (300 MN /, ^ Μ δΟ-ά ₆ , 300 K): δ [ppm] = 9.73 (δ, 1Η), 8.18 (ά, 1Η), 7.67 (ά, 1Η), 7.56 (δ, 1Η), 7.38-7.30 (t, 1Η), 7.12-7.05 (t, 1Н), 6.95-6.87 (t, 1Н), 6.77 (δ, 1Н), 4.37-4.25 (t, 2Н), 3.80 (δ, 3Н), 3.69 (δ, 1H), 2.87 (δ, 3H), 2.35 (δ, 3H).

Example 33: (-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(δ-methylsulBphonimidoyl) methyl] pyridin-2-yl} pyridin-2- amine

¹ H NMR (300 MN /, ^ Μ δΟ-ά ₆ , 300K): δ [ppm] = 9.73 (δ, 1H), 8.18 (ά, 1H), 7.67 (ά, 1H), 7.56 (δ, 1H), 7.37-7.31 (t, 1H), 7.12-7.06 (t, 1H), 6.95-6.87 (t, 1H), 6.77 (δ, 1H), 4.37-4.25 (t, 2H), 3.80 (δ, 3H), 3.69 (ά, 1H), 2.87 (δ, 3H), 2.35 (δ, 3H).

Alternative to Example 32: (+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -X- {6-methyl-4- [Щ methylsulBphonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine

(+) - 2,2,2-trifluoro-X - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6methylpyridin-4-yl ) methyl] (methyl) -λ ⁴ -sulBfanilidene} acetamide (300 mg; 0.602 mmol; intermediate 4.7) was dissolved in methanol (36.0 ml) and water (18.0 ml). At 0-5 ° C, the pH was adjusted to 9-10 using an aqueous solution of potassium hydroxide (15%). At this temperature, Ο \ ο ^ ® (315.0 mg; 0.512 mmol) was added in several parts, and the pH was adjusted in the range of 9-10. The mixture was stirred for 1 h at 0-5 ° C, and the pH was adjusted to 9-10.

The pH in the mixture was adjusted to pH 6-7 using 2.0 M hydrochloric acid. A saturated aqueous solution of sodium chloride was added, and the reaction mixture was extracted three times with dichloromethane. The mixed organic layers were washed with an aqueous solution of thiosulfate (10%), dried over magnesium sulfate and concentrated.

Five such samples were combined and purified using silica gel column chromatography (gradient: dichloromethane to dichloromethane / ethanol 9: 1) to obtain the desired product (800 mg; 1.91 mmol).

[α] _ο ²⁰ + 11.4 ° (1.00, ^ ΜδΟ).

¹ H NMR (300 MN /, □ λ-ΙδΟ-ώ ,, 300K): δ [ppm] = 9.75 (δ, 1H), 8.20-8.17 (t, 1H), 7.67 (ά, 1H), 7.59-7.55 (t, 1H), 7.38-7.30 (t, 1H), 7.13-7.06 (t, 1H), 6.95-6.87 (t, 1H), 6.77 (δ, 1H), 4.38-4.25 (t, 2H), 3.80 (δ, 3H), 3.71 (δ, 1H), 2.87 (δ, 3H), 2.35 (δ, 3H).

Alternative to Example 33: (-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -X- {6-methyl-4 - [^ methylsulBphonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine

(-) - 2,2,2-trifluoro-X - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6methylpyridin-4-yl ) methyl] (methyl) -λ ⁴ -sulBfanilidene} acetamide (296 mg; 0.594 mmol; intermediate 4.8) was dissolved in methanol (35.5 ml) and water (17.8 ml). At 0-5 ° C, the pH was adjusted to 9-10 using an aqueous solution of potassium hydroxide (15%). At this temperature, Οχο ^ ® (310.0 mg; 0.505 mmol) was added in several parts, and the pH was adjusted in the range of 9-10. The mixture was stirred for 1 h at 0-5 ° C, and the pH was adjusted to 9-10.

The pH in the mixture was adjusted to a pH of 6-7 using 2.0 M hydrochloric acid. A saturated aqueous solution of sodium chloride was added, and the reaction mixture was extracted three times with dichloromethane. 89 027226. The mixed organic layers were washed with an aqueous solution of thiosulfate (10%), dried over magnesium sulfate and concentrated.

Five such samples were combined and purified using silica gel column chromatography (gradient: dichloromethane to dichloromethane / ethanol 9: 1) to obtain the desired product (800 mg; 1.91 mmol). [α] _ο ²⁰ = -14.0 ° (1.00, OMZO).

¹ H NMR (400 MP Ιζ, PM8O _6th , 300K): δ [ppm] = 9.75 (s, 1Η), 8.19 (s, 1Η), 7.68 (s, 1Η), 7.58 (s, 1Η), 7.35 (yy, 1Η), 7.09 (yy, 1Η), 6.92 (y ± t, 1Η), 6.78 (h, 1Η), 4.38-4.27 (t, 2Η), 3.81 (h, 3Η), 3.71 (h, 1Η ), 2.88 (s, 3Η), 2.36 (s, 3Η).

In the following table. 1 summarizes the compounds described in the Examples section.

Table 1

Example No. Structure Connection Name one ΗΝ About 9 ^ (gas) -5-fluoro-4- (4-fluoro-2- methoxyphenyl) -2Y- {4 - [(5-methyl- sulfonimide oyl) methyl] pyridin-2- il} pyridin-2-amine 2 ΗΝ About 9 ^ (+) - 5-fluoro-4- (4-fluoro-2- methoxyphenyl) -A- {4 - [(5-methyl- sulfonimide oyl) methyl] pyridin-2- il} pyridin-2-amine 3 ΗΝ O Ν C <'' ^ζ ' (-) - 5-fluoro-4- (4-fluoro-2- methoxyphenyl) -A- {4 - [(5-methyl- sulfonimide oyl) methyl] pyridin-2- il} pyridin-2-amine 4 ΗΝ O D (gas) -5-fluoro-4- (4-fluoro-2- methoxyphenyl) -L / - {6-methyl-4 - [(5- methylsulfonimidoyl) methyl] pyrid in-2-yl} pyridin-2-amine

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5 A x ΗΝ 0 Ν Ν 0 (gas) -5-bromo-A- [5-fluoro-4- (4-fluoro-2- methoxyphenyl) pyridin-2-yl] -6- methyl 4 - [(5-methyl sulfone- imidoyl) methyl] pyridin-2-amine 6 ΗΝ 0 SU U (gas) -5-fluoro-4- (4-fluoro-2- methoxyphenyl) -A- {6-methoxy-4 - [(5- methylsulfonimidoyl) methyl] pyrid in-2-yl} pyridin-2-amine 7 C1 ΗΝ 0 SU D LAL _Y LL ^ (gas) -U- {6-chloro-4- [(5- methylsulfonimidoyl) methyl] pyrid in-2-yl] -5-fluoro-4- (4-fluoro-2- methoxyphenyl) pyr id in-2-amine 8 ΗΝ 0 ί ^ + Ν W.? ^X ' ^h ''1 N N 1 Ι (gas) -2- {5- [(2- {[5-fluoro-4- (4-fluoro-2- methoxyphenyl) pyridin-2- il) amino} pyr id in-4-yl) methyl] - sul f onimi d oil} ethanol nine ΗΝ Oh Ι ^^, Ν? ^X '' ^{Ζ /} 1 II 11 1 1 (gas) -A- (4 - {[5- (2- aminoethyl) sulfonimide oil] methyl} pyridin-2-yl) -5-fluoro-4- (4-fluoro-2- methoxyphenyl) pyr id in-2-amine 10 \, ° Γ | ΐ ίΥ C / AA-id {[(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyrid in-4-yl) methyl] (methyl) oxide-7 ⁶ -sulfan silt ideas} cyanamide (single stereoisomer); eleven \ “° \ χχ χ ^ Α χ TO? Г ιΐ ΐιΓ 1 0 χβ ^ Λ, ΛΛΥ, (gas) ethyl {[(2- {[5-fluoro-4- (4-fluoro-2- methoxyphenyl) pyridin-2-yl] amino} - pyridin-4-yl) methyl] (methyl) oxide -

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X ⁶ -sulfanylidene} carbamate 12 Ν ρ Ο ΐΓΤ ι (gas) -1-ethyl-3 - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyrid in-4-yl) methyl] (methyl) oxide-X ⁶ sulfanyl ideas} urea thirteen ϊη, ° η ΥτΎ (gas) -A- {[(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyrid in-4-yl) methyl] (methyl) oxide -X ⁶ sulfanyl ideas} acetamide 14 HC1 ΗΝ Ο ^, Ν Ν ^ < ^Γ ? ^Χ Λ '/ 5-fluoro-4- (4-fluoro-2-methoxyphenyl) - Ν- {4- [(5-methylsulfonimidoyl) - methyl] pyrid in-2-yl} pyrid in-2- amine hydrochloride; enantiomer 2 fifteen \ ~ ° \ X> Υν, ° g ίί ΐι 1 ΐ (gas) ethyl {[(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} - 6-methoxypyridin-4-yl) methyl] - (methyl) oxide-X ⁶ - sulfiline} carbamate sixteen HC1 ΗΝ Ο ^, Ν Ν ^ ν ^Ρ θ ' 5-fluoro-4- (4-fluoro-2-methoxyphenyl) - Ν- {4- [(5-methylsulfonimidoyl) - methyl] pyrid in-2-yl} pyrid in-2- amine hydrochloride; enantiomer 1 17 Ρ ην ο μ'Υ η ^ Υ ^ Y (gas) -5-fluoro-4- (4-fluoro-2- methoxyphenyl) -A- {6-fluoro-4- [(5- methylsulfonimidoyl) methyl] pyrid in-2-yl} pyridin-2-amine

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Ρ Α (gas) -2,2,2-trifluoro- / Y- {[((2-φτορ-6- eighteen ^ρ g Τ Ν Ο Κ * Ν β L {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) - Ιί V Μ pyridin-2-yl] amino} pyridin-4- Η υ ^ν Ρ il) methyl] (methyl) oxide-X ⁶ sulfanyl ideas} acetamide Ρ (+) - 5-fluoro-4- (4-fluoro-2- nineteen ^ΗΝ Α ν ' ‘Ν II Ν ' || ζΡ methoxyphenyl) -L / - {6-fluoro-4- [(5- Ά, II Ί \ Γ Η Ίι methylsulfonimidoyl) methyl] pyrid Α * ⁴ Ρ in-2-yl} pyridin-2-amine Ρ (-) - 5-fluoro-4- (4-fluoro-2- twenty ΗΝ Ο ν ' ‘Ν Ν ' X ζΡ methoxyphenyl) -L / - {6-fluoro-4- [(5- β— Ί \ Γ Η CHA * Ίι methylsulfonimidoyl) methyl] pyrid ⁴ Ρ in-2-yl} pyridin-2-amine 21 Ρ ,one , ρ (gas) -5-fluoro-4- (4-fluoro-2- methoxyphenyl) -L / - {4 - [(5- ΗΝ 0 V * Ν Ν ' X X A ⁴ methylsulfonimidoyl) methyl] -6- Η ΤΓ Ί Α ⁴ ‘Γ (trifluoromethyl) pyridin-2- Γ silt} feast idin-2-amine 22 Ρ ,one , ρ (+) - 5-fluoro-4- (4-fluoro-2- methoxyphenyl) -L / - {4 - [(5- ΗΝ 0 V * Ν Ν ' \\ 'ζ /BUT X X 'Ν ^ ⁴ A ⁴ methylsulfonimidoyl) methyl] -6- Η ΤΓ Ί Α ⁴ * η (trifluoromethyl) pyridin-2- Γ silt} feast idin-2-amine Ρ R.E. ,one (-) - 5-fluoro-4- (4-fluoro-2- 23 ΗΝ 0 V * Ν Ν ' , Ρ methoxyphenyl) -L / - {4 - [(5- /BUT X X 'Ν ^ ⁴ A ⁴ methylsulfonimidoyl) methyl] -6- Η ΤΓ Ί Α ⁴ ‘Γ (trifluoromethyl) pyridin-2- Γ silt} feast idin-2-amine

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24 Ρ rsch><^. 0 ν% ° χ ⁸ χ Ρ ΡΛ Γ * , Ρ Ν 1 ^ ν ' Η V q y L (+) - 2,2,2-trifluoro-A - [{[2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} - 6- (methyl trifluoro ) - pyridin-4-yl] methyl} (methyl) oxoX ⁶ -sulfonyl idea] acetamide Ρ rsch Ρ ΡΛ , Ρ (-) - 2,2,2-trifluoro-A - [{[2 - {[5-fluoro-4- 25 ν γ ⁵ % ° Γ * Ν II Ν ^% II q y (4-fluoro-2-methoxyphenyl) pir idin-2- χ ⁸ χ ν ' UL Υί silt] amino} - 6- (methyl trifluoro) - and. _R pyridin-4-yl] methyl} (methyl) oxoX ⁶ -sulfan yl ideas] acetamide 26 Ρ (gas) -4- (2-ethoxy-4-fluorophenyl) -5- ^Η % ° D \ - ~ \ II Ν ] | ^: fluoro-U- {6-fluoro-4- [(5- 'ν Η _>> DV l methyl sulfonimidoyl) methyl] pyr id in-2-yl} pyridin-2-amine 27 ^ν , ..? Ρ Γ 'Ν ί [ Ν ^ Νγ II X (gas) -A- {[(2- {[4- (2-ethoxy-4-fluoro- phenyl) -5-fluoropyridin-2-yl] amino} - Χ ⁵ Χ Χ ^ ϋ> * Ι \ Γ Η ΪΊ 6-fluoropyridin-4-yl) methyl] - Mch _r (methyl) oxide-X ⁶ -sulfan yl ideas} 2,2,2-trifluoroacetamide Ρ (+) - 4- (2-ethoxy-4-fluorophenyl) -5-fluoro- 28 ^Η % ° D \ - ~ \ II Ν l '' Chg '' ^: A- {6-fluoro-4 - [(5- 'Ν Η _>> DV l methyl sulfonimidoyl) methyl] pyr id in-2-yl} pyridin-2-amine Ρ (-) - 4- (2-ethoxy-4-fluorophenyl) -5-fluoro- 29th ^Η % ° D \ - ~ \ II Ν ] | ^: A- {6-fluoro-4 - [(5-methylsulfon- ⁴ Ν _>> DV imide oyl) methyl] pyridin-2- Η Ος silt} feast idin-2-amine ΗΝ 0 _X P „/ (gas) -A- {4- [(5-ethylsulfonimidoyl) - thirty ⁴ Ν ^Χ UL P methyl] pyridin-2-yl} -5-fluoro-4- (4- its fluoro-2-methoxyphenyl) pir idin-2- amine

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31 R. V ,R ‘Ν to F BUT N Ld (gas) -A- {6- (difluoromethyl) -4 - [(5- methylsulfonimidoyl) methyl] pyrid in-2-yl} -5-fluoro-4- (4-fluoro-2- methoxyphenyl) pyr id in-2-amine L I (+) - 5-fluoro-4- (4-fluoro-2- ΗΝ Oh At F N about 32 L d F ^ ^ H <h methoxyphenyl) -A- {6-methyl-4 - [(5- N 1a methyl sulfonimidoyl) methyl] pyr id in-2-yl} pyridin-2-amine L I (-) - 5-fluoro-4- (4-fluoro-2- ΗΝ Oh V F N cg 33 L d F ^ ^ H <h methoxyphenyl) -A- {6-methyl-4 - [(5- N 1a methyl sulfonimidoyl) methyl] pyr id in-2-yl} pyridin-2-amine

Results.

Tab. 2: inhibition of C1G9 and C1G2 by the compounds of the present invention.

The values of Yuzo (concentration of half-maximal inhibition) are indicated in nmol, nt means that no compounds were tested in this assay.

F: Example number

SOK9: Analysis by SOK9 / SucT1 kinase as described for Method 1a. in the section "Materials and Methods".

<3>: SOK2: Analysis of SOK2 / Sous kinase as described for

Method 2. in the section "Materials and Methods".

©: SOK9, at high ATP concentrations: Analysis by SOK9 / CusT1 kinase as described for Method 1b. in the section "Materials and Methods".

©: SOK2, at high ATP concentrations: Analysis by SOK2 / ССЕ kinase as described for Method 2b. in the section "Materials and Methods".

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table 2

Φ Structure ® © © © one ΗΝ O ΝO ^X 4 410 10 5860 2 ™ „р Щ Щ ΐ, ^ ν ^Ρ К 3 360 4 2920 3 ^н + р Щ ΐ, ^ ν ^Ρ К х ^ ФДТфД 2 240 3 2490 4 ΗΝ Oh γΎ 0 ^ 4 120 2 1010 5 ^Br \ ^ X / ΗΝ O DT N Y, 4 ^x 9 5 140 3 1770 6 ΗΝ Oh Ν N 0 ^ S'g 2 4 one 84 7 ΗΝ Oh ί ^ Ν Ν ^ < ^Ρ (/ 2 44 2 630 8 ΗΝ 0 Γ ^ Ν 0 ^Χ * '/ thirteen 430 14 4190

- 96 027226

nine ΗΝ 0 (^ 'Ν''''1 11 11 1 1 ι / ⁴ ' · '' 8 240 6 4230 10 \ Ο Χ, Ν Ν ^ 1 < ^Ρ θ ' 4 72 one 1420 eleven 4 Χΐ ^> X Η ,? Ηΐ <Υ ι one 170 one 2920 12 Μ _Ρ Η ,? ΓΥ < 2 140 2 3070 thirteen ° ° Ο ϊΓνν о х- ^ ЧА „АА ^ у one 130 one 3690 14 HC1 ΗΝ O (Y) Ν, Ή θ ' 3 200 one 3410 fifteen ° N? G ϊϊ GI G about 2 10 one 123 sixteen HC1 ΗΝ O Χ.Ν Ν, Χ <θ ' xxX ^ AX ^ A ^ 3 430 8 5150 17 R ΗΝ About 0% CID θ ' 0.9 49 1.8 886

- 97 027226

eighteen ^ r ° 1 ρ B a sg d 3 39 4 Η.Τ. nineteen R ΗΝ About X ζ '· ΆΛ „ΛΛ ^ 5 94 nineteen 1370 twenty Ρ ^Η Υ ° Γ ιϊ ϊιΑΗ 2 72 one 815 21 _p Ρ _p ΗΝ 0 Υ ' ^{χ /} ' 2 eleven 2 133 22 _p Ρ _p Υ ° Γ ιΐ ϊΓΑ ζδΑΛ, ΛΛ ^ 2 eighteen one 233 23 _p Ρ _p γ ° g ιΐ ΐΓΑ 2 22 2 283 24 ^Ν ° r ιϊ ΓΓΎ eighteen 250 27 4000

- 98 027226

25 GL about F N O O '' '' II II 1 fifteen BY thirteen 2640 26 R ^N T „° G and V 3 by 4 1200 27 BUT r ιϊ ϊι ^ Γ? nine 1200 22 20000 28 P ^N % ° G || || ^ Υ ^Ρ 9 ^ 5 120 4 1170 29th P ΗΝ, Ρ Ρ, '; ¹ Ν 3 98 4 1710 thirty ΗΝ Oh ί ’^, Ν 9 ^ 3 210 5 300 31 ΗΝ About 9 ^ 3 10 one 229 32 ΗΝ about 9 ^ \ 'Ζ / nt 120 2 1120

33 NOT G ‘Ν Ν ' ίί D Η Ή- Η.Τ. 67 one 680 Ρ

Tab. 3a and 3b: inhibition of cell proliferation ^ ba, Ηе ^ а-ΜаΤи-А ^ К, ΝΟ-Η460, Όυ145, Сасо-2, В16Р10, А2780 and МОМ-13 by the compounds of the present invention when determined in accordance with the description for method 3 , in the section Materials and methods. All ΚΑ ₀ values (half maximal inhibition concentration) are indicated in nmol, nt means that no compounds were tested in this assay.

©: Example No. ©: Inhibition of cell proliferation of HePa ® cells: Inhibition of cell proliferation of HePa-MaTi-AIK ©: Inhibition of cell proliferation of IS1-H460 ©: Inhibition of cell proliferation of AI 145 ©: Inhibition of cell proliferation of Caco-2 ©: Inhibition of cell proliferation of Bac10-© : Inhibition of cell proliferation A2780 ®: Inhibition of cell proliferation MORM-13

- 99 027226

Table 3 a

Indication for use for cell lines

Cell line A source Indication for use Nea ATCC Human cervical tumor ΝΟΙ-Η460 ATCC Non-small cell lung carcinoma A2780 ECACC Human Ovarian Carcinoma ϋυ 145 ATCC Hormone-independent prostate carcinoma human glands Nea-MaTi-ΑϋΚ EPO-OTH Berlin Multi-Resistant Cervical Carcinoma of man Saso-2 ATCC Human Colorectal Carcinoma

B16E10 ATCC Mouse melanoma MOM-13 ϋδΜΖ Acute myelocytic leukemia in humans

Table 3b

Proliferation Inhibition

© Structure ® © © © © © ® ® one ΗΝ O TT L 95 61 62 37 45 BY 26 nineteen 2 by 33 75 33 62 240 BY 29th 3 ΗΝ About Υ® L one hundred 37 65 37 58 310 52 40 4 ΗΝ About ρ Ν ΥΤΥ L \ 'Ί 35 34 97 67 68 one hundred 37 35 5 HF L ^ Λ i ΗΝ Oh Oh 93 nt 120 by BY 120 nt nt 6 ⁿ f „° g | 7 V L 21 thirty 33 thirty 31 33 eleven eleven 7 ΗΝ About ρ N L 32 32 47 37 41 34 27 28

- 100 027226

8 ΗΝ 0 ί ^ Ν 140 200 290 by 160 186 45 55 nine ην about ι ^ Χν? ^Χ 410 nt nt nt nt nt 210 120 10 X χ \, ^: % ° Γ ^ ιϊ ΐιΓ ΐ 31 32 39 34 38 63 10 12 eleven ° Η „ρ Ο ϊΧΓΤ 0 72 one hundred BY BY BY 180 23 42 12 \ _Η η% ° π ϊ, V? ^χ 34 one hundred one hundred 77 98 130 26 29th thirteen Χ ^Ν ν /, ° η ΐ, ν 0 χ3 ^ Λ, ΛΛχ <^ one hundred by BY BY 120 180 23 29th 14 HC1 ΗΝ Ο Γ ^, Ν 9 ^ 42 46 thirty 33 37 73 nt nt fifteen Do% ° g ιϊ? GT ^P ? ^χ o x ^ al / d 40 31 32 31 39 45 nt nt sixteen HC1 ΗΝ Ο ί '^ Ν C ^ ” ⁵ ^ ¹³ 9 ^ /xLL.CD 63 by 130 120 120 150 nt nt

- 101 027226

17 Ρ ^Η % ° Γ ιΐ || ^ γ ^Ρ 9 46 33 45 48 57 67 14 twenty eighteen 0 λ ρ B Α γυ < 61 35 110 41 43 68 Η.Τ. Η.Τ. nineteen P ΗΝ O Γ ^ Ν Ν ^ ⁵ '^' ³ 0 / AL.LDD Η.Τ. 64 110 58 Η.Τ. 95. Η.Τ. Η.Τ. twenty Ρ ΗΝ Ο γ'Ν 0 thirty 38 one hundred 58 45 54 Η.Τ. Η.Τ. 21 Ρ Ρ Ρ ^Η φ, ° Γ Η ΐ, Α ^Ρ 29th thirty 33 thirty 32 38 17 17 22 _ρ Ρ ^Η φ, ° Γ Η ΐΑ '/ χζν, Λ / Д thirty thirty 34 32 38 51 12 10 23 _p Ε _p ^Η φ, ° Γ Η ΐΑ '/ χζν, Λ / Д thirty thirty 35 34 34 47 eleven 10

- 102 027226

Tab. 4: thermodynamic solubility of the compounds of the present invention in water at pH 6.5 and in an aqueous solution of citrate buffer, which is usually used in clinical dosage forms for intravenous administration, when determined by analysis of equilibrium solubility in a shake flask, in accordance with the description for method 4, in Materials and methods section.

F: Number of Example ©: Solubility in water at pH 6.5 in mg / L ©: Solubility in mg / L in an aqueous solution of citrate buffer, pH4

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Table 4

© Compound structure ® Θ one ΗΝ About 9 ^ \ '// thirteen 489 2 ΗΝ Ο 9 ^ \ '// 25 Η.Τ. 3 ΗΝ Ο 9 ^ 27 699 4 ΗΝ 0 γ'Ν 0 ^ Η.Τ. 470 8 ΗΝ 0 ί ^ Ν Ν ^ 4 < ^Γ Ο ^Χ Η.Τ. 730 nine ΗΝ 0 (^ 'Ν Ο ^Χ '' ^Ζζ 1 II 11 1 1 η ₂ ν ^^ Η.Τ. 660 10 ο Γ ^ ν ν ^ ϊυ ^ ο ^χ Η.Τ. 102 eleven 9 Χΐ ^ © X N "? Γ ^ ιϊ ϊΓΤ ι 0 χβ ^ Λ, ΛΛ ^ Η.Τ. 185 12 \ _ Η Ίη, ° Γϊ ϊΓτν Oh χΝ ^ Α ,, ΑΧγΛ ^ Η.Τ. 34 14 HC1 ΗΝ Ο Γ ^ Ν Ν ^ γ Ο ^Χ '' ^ζ 'χ5 ^ Λ, Λ ^ χ ^ Η.Τ. 600 17 Ρ ΗΝ Ο Γ ^ Ν С <х-> чА _й ХЛ ^ Η.Τ. 3

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22 ^N A, p G ιι ΐι V Ch 'xxX \ AAD. nt 52 23 hg ^ng and ° g. ΐ ϊ, V nt 45

Tab. 5: Caco-2 permeability test of the compounds of the present invention, as determined in accordance with the description for method 5, in the Materials and Methods section.

F: Example Number @: Concentration of test compound in µmol.

Θ: P _arr AB (Msh), indicated in [nm / sec.]

Rarr B-A (Mal), indicated in [nm / sec.] ®: Efflux coefficient

Table 5

F Compound structure ® ® © © one ΗΝ Oh 2 155 180 1.16 2 ΗΝ Oh ί ^ Ν / xxHAAD 2 166 186 1.12 3 ΗΝ Oh \ '// 2 133 197 1.48

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4 ΗΝ O G'U 2 196 149 0.76 8 ΗΝ ABOUT 2 41 246 6 17 R ΗΝ O γ'Ν (< 2 141 135 0.96 21 r _p Ά, ° Г ιΐ MF 2 51 33 0.64 22 R ΗΝ O Γ ^ .Ν A 2 48 53 1.1 23 Ά, ° Г ιΐ ΐι V 2 47 62 1.3 thirty ΗΝ Oh Α. ¹ ) ¹ A 2 186 172 0.92

Tab. 6: inhibition of carbonic anhydrase-1 and carbonic anhydrase-2 by the description for method 6 in the Materials and methods section.

F: Compound number ®: Inhibition of carbonic anhydrase-1: half-maximal inhibition values) are indicated in nmol.

(3): Inhibition of carbonic anhydrase-2: half-maximal inhibition values) are indicated in nmol.

when determined in accordance with

1C ₅₀ (concentration

1 Szo (concentration

Table 6

F Compound structure © (3) one ΗΝ О Г ^ н П ^ ф ^Р Г > 10,000 > 10,000

- 106 -

Claims (16)

CLAIM 1. The compound of General formula (I) where K ¹ represents a C ₁ -C ₆ -alkyl group, where the specified group, if necessary, is substituted by one substituent selected from the group of hydroxy, C ₁ -C ₃ -alkoxy, -X ₂ , alkylamino, dialkylamino or cyclic amines; K ² represents a group selected from K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a methyl, methoxy, difluoromethyl or trifluoromethyl group; K ⁴ represents a hydrogen atom or a bromine atom; K ⁵ represents a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —C (O) XK ¹⁰ K ¹¹ ; K ⁶ , K ⁷ represent, independently from each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom; K ⁸ represents a C ₁ -C ₃ alkyl group; K ⁹ represents a C ₁ -C ₃ alkyl group, a benzyl group or trifluoromethyl; K ¹⁰ , K ¹¹ represent, independently of each other, a group selected from hydrogen, C ₁ -C ₂ alkyl; as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of the compound. 2. The compound of general formula (I) according to claim 1, characterized in that K ¹ represents a C1-C3 alkyl group, wherein said group is optionally substituted with one substituent selected from the hydroxy group, —X ₂ ; K ² represents a group K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a methyl, methoxy, difluoromethyl or trifluoromethyl group; K ⁴ represents a hydrogen atom or a bromine atom; K ⁵ represents a group selected from a hydrogen atom, cyano, —C (O) K ⁹ , —C (O) OK ⁹ , —C (O) XK ¹⁰ K ¹¹ ; K ⁶ represents a fluorine atom; K ⁷ represents hydrogen; K ⁸ represents a methyl or ethyl group; K ⁹ represents methyl, ethyl or trifluoromethyl groups; K ¹⁰ , K ¹¹ represent, independently of each other, a group selected from hydrogen, C ₁ -C ₂ alkyl; as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of the compound. 3. The compound of General formula (I) according to claim 1, characterized in that K ¹ represents methyl, ethyl, 2-hydroxyethyl or 2-aminoethyl groups; - 107 027226 K ² represents a 4-fluoro-2-methoxyphenyl or 4-fluoro-2-ethoxyphenyl group; K ³ represents a hydrogen atom, a fluorine atom or a chlorine atom or a methyl, methoxy, difluoromethyl or trifluoromethyl group; K ⁴ represents a hydrogen atom or a bromine atom; K ⁵ represents a hydrogen atom or a group selected from cyano, —C (O) CH ₃ , —C (O) CP ₃ , —C (O) OC ₂ H, —C (O) S (H) C ₂ H ₅ ; as well as enantiomers, diastereoisomers, salts, solvates or salts of solvates of the compound. 4. The compound according to claim 1, which is (gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {4 - [(§-methylsulfonimidoyl) methyl] pyridin-2yl} pyridine- 2-amine; (+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {4 - [(§-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine; (-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {4 - [(§-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine; (gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-methyl-4 - [(§-methylsulfonimidoyl) methyl] pyridin2-yl} pyridin-2-amine; (gas) -5-bromo-Y- [5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] -6-methyl-4 - [(§methylsulfonimidoyl) methyl] pyridin-2- amine; (gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-methoxy-4 - [(§methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin-2-amine; (gas) -Y- {6-chloro-4 - [(§-methylsulfonimidoyl) methyl] pyridin-2-yl} -5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-amine; (gas) -2- {§ - [(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin-4yl) methyl] sulfonimidoyl} ethanol; (gas) -Y- (4 - {[§- (2-aminoethyl) sulfonimidoyl] methyl} pyridin-2-yl) -5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-amine; {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin-4-yl) methyl] (methyl) oxoX ⁶ -sulfanylidene} cyanamide; (gas) ethyl {[(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin-4yl) methyl] (methyl) oxide-X ⁶ -sulfanylidene } carbamate; (gas) -1-ethyl-3 - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin-4yl) methyl] (methyl) oxide -X ⁶ -sulfanylidene} urea; (gas) -Y - {[(2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} pyridin-4yl) methyl] (methyl) oxide-X ⁶ - sulfanylidene} acetamide; 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {4 - [(§-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin2-amine hydrochloride; enantiomer 2; (gas) ethyl {[(2- {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6-methoxypyridin-4yl) methyl] (methyl) oxide-X ^6- sulfanilidene} carbamate; 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {4 - [(§-methylsulfonimidoyl) methyl] pyridin-2-yl} pyridin2-amine hydrochloride; enantiomer 1; (gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-fluoro-4 - [(§-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine; (gas) -2,2,2-trifluoro-L - {[(2-fluoro-6 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2yl] amino} pyridin-4- yl) methyl] (methyl) oxide-X ⁶ -sulfanylidene} acetamide; (+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-fluoro-4 - [(§-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine; (-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {6-fluoro-4 - [(§-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine; (gas) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {4 - [(§-methylsulfonimidoyl) methyl] -6 (trifluoromethyl) pyridin-2-yl} pyridin-2-amine; (+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {4 - [(§-methylsulfonimidoyl) methyl] -6 (trifluoromethyl) pyridin-2-yl} pyridin-2-amine; (-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -Y- {4 - [(§-methylsulfonimidoyl) methyl] -6 (trifluoromethyl) pyridin-2-yl} pyridin-2-amine; (+) - 2,2,2-trifluoro-L - [{[2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6 (trifluoromethyl) - pyridin-4-yl] methyl} (methyl) oxide-X ⁶ -sulfanylidene] acetamide; (-) - 2,2,2-trifluoro-L - [{[2 - {[5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl] amino} -6 (trifluoromethyl) - pyridin-4-yl] methyl} (methyl) oxide-X ⁶ -sulfanylidene] acetamide; (gas) -4- (2-ethoxy-4-fluorophenyl) -5-fluoro-L- {6-fluoro-4 - [(§-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine; - 108 027226 (γ ^) - Ν - {[(2- {[4- (2-ethoxy-4-fluoro-phenyl) -5-fluoropyridin-2-yl] amino} -6-fluoropyridin-4yl) methyl] (methyl) oxide-X ⁶ -sulfanylidene} -2,2,2-trifluoroacetamide; (+) - 4- (2-ethoxy-4-fluorophenyl) -5-fluoro-N- {6-fluoro-4 - [(8-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine; (-) - 4- (2-ethoxy-4-fluorophenyl) -5-fluoro-N- {6-fluoro-4 - [(8-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine; (^ ac) -N- {4 - [(8-ethylsulfonimidoyl) methyl] pyridin-2-yl} -5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-amine; (^ ac) -N- {6- (difluoromethyl) -4 - [(8-methylsulfonimidoyl) methyl] pyridin-2-yl} -5-fluoro-4- (4-fluoro-2methoxyphenyl) pyridin-2-amine; (+) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(8-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine; (-) - 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(8-methylsulfonimidoyl) methyl] pyridin-2yl} pyridin-2-amine, as well as enantiomers , diastereoisomers, salts, solvates or salts of solvates of said compound. 5. The use of the compounds of general formula (I) according to any one of claims 1 to 4 for the treatment and / or prevention of hyperproliferative diseases, viral infections and / or diseases of the cardiovascular system. 6. The use of the compounds of general formula (I) according to any one of claims 1 to 4 for the treatment and / or prevention of lung carcinoma, prostate carcinoma, cervical carcinoma, colorectal carcinoma, melanoma, ovarian carcinoma or leukemia. 7. A pharmaceutical combination for treating and / or preventing hyperproliferative diseases, viral infections and / or diseases of the cardiovascular system, comprising a compound according to any one of claims 1 to 4 in combination with at least one or more additional active ingredients. 8. A pharmaceutical composition for treating and / or preventing hyperproliferative diseases, viral infections and / or diseases of the cardiovascular system, comprising a compound according to any one of claims 1 to 4 in combination with an inert, non-toxic pharmaceutically acceptable excipient. 9. An SEC9 kinase inhibitor, which is a compound of formula (I) according to any one of claims 1 to 4. 10. The compound of General formula (5) where K ¹ , K ² , K ³ and K ⁴ have the meanings as defined in accordance with any one of claims 1 to 3 for compounds of General formula (I), or a salt, MES or MES salt the specified connection. 11. The compound of General formula (6) where K ¹ , K ² , K ³ and K ⁴ have the meanings as defined in accordance with any one of claims 1 to 3 for compounds of the general formula (I), or also the enantiomer, diastereoisomer, salt a solvate or a solvate salt of said compound. 12. The compound of General formula (14) - 109 027226 where K ¹ , K ³ and K ⁴ are as defined in accordance with any one of claims 1 to 3 for compounds of the general formula (I); YO means a leaving group, or also an enantiomer, diastereoisomer, salt, solvate or solvate salt of said compound. 13. The compound of General formula (16) where K ¹ , K ³ and K ⁴ have the meanings as defined in accordance with any one of claims 1 to 3 for compounds of General formula (I); YO means a leaving group, or also an enantiomer, diastereoisomer, salt, solvate or solvate salt of said compound. 14. The method of obtaining the compounds of formula (6), where K ¹ , K ² , K ³ and K ⁴ have the meanings as defined for the compound of formula (I) according to any one of claims 1 to 3, in which the compound of formula (5) where K ¹ , K ² , K ³ and K ⁴ have the meanings as defined for the compound of formula (I) according to any one of claims 13, are reacted with trifluoroacetamide and 1,3-dibromo-5,5-dimethylhydantoin in the presence of an alkaline salt tert-butanol metal in cyclic ether as a solvent to give a compound of formula (6) and wherein the obtained compound, if necessary, in an appropriate case ae is converted using the appropriate (ΐ) solvents and / or (ίί) bases or acids to give the solvates, salts and / or solvates of salts of said compound. 15. The method of obtaining the compounds of formula (I) according to any one of claims ¹ to ⁴ , wherein the compound of formula (6) wherein K ¹ , K ² , K ³ and K ⁴ are as defined for the compound of formula (I) according to any of claims 13, oxidised using manganese acid alkali metal salt in an aliphatic ketone of formula C1-C ₂ -C (O) _-C1-C2 alkyl as solvent, followed by, if trifluoroacetyl group present in the compound of formula ( 6), did not split during the above oxidation process, removing said trifluoroacetyl group by treatment the resulting intermediate with an appropriate base in an alcoholic solvent to give a compound of the formula (I) where K ⁵ is hydrogen, and wherein the resulting compound, if necessary, is, if necessary, converted using the appropriate (ΐ) solvents and / or (ΐΐ) bases or acids to obtain solvates, salts and / or solvates of salts of said compound. 16. A method of obtaining a compound of formula (I) according to any one of claims 1 to 4, wherein 3, is oxidized using a peroxomonosulfate-based oxidizing agent in a solvent selected from an aliphatic alcohol of the formula C ₁ -C ₃ -alkyl-OH, water and X, X-dimethylformamide, or a mixture of these compounds, to obtain a compound of formula (I) where K ⁵ is hydrogen, and in which case the resulting compound, if necessary, is subjected to conversion using appropriate (ΐ) solvents and / or (ΐΐ) bases or acids to obtain solvates, salts and / or solvates of salts of said compound.